The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; 4 of the 45 sources its claims cite were checked for support.
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
Open accessAbstract
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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76 Own result · 28 Not checked yet · 19 Own method · 17 Own interpretation · 1 Supported
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In the paper
“The realization that a positive association exists between an MPR (≤10% viable tumor in resected tumor specimens) to neoadjuvant chemotherapy and improved survival outcomes in patients with operable NSCLC4–7”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Introduction
What the sources say
- Supportedcites [4] Pataer, A. et al. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J. Thorac. Oncol. 7, 825–832 (2012). source
The Abstract Results report that, among 192 patients with resected NSCLC who received neoadjuvant chemotherapy, those with ≤10% residual viable tumor had significantly better overall and disease-free survival than those with >10%. The Discussion also states that this histopathologic response predicted overall survival after adjustment for pathologic stage. (LLM, conf=0.94)
- Supportedcites [5] Hellmann, M. D. et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 15, e42–e50 (2014). source
Section 7 states that MPR following neoadjuvant chemotherapy is associated with overall survival in patients with resectable NSCLC and defines MPR as ≤10% residual viable tumor. Section 2 also describes the association between MPR and improved survival as consistent across studies, while noting that larger validation studies are needed. (LLM, conf=0.94)
- Supportedcites [6] Chaft, J. E. et al. Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers. J. Thorac. Oncol. 8, 1084–1090 (2013). source
The Results (Exploratory Outcomes) report that resected patients with ≥90% pathologic response had significantly better three-year recurrence-free and overall survival than those with less response. The Discussion defines this response as more than 90% treatment effect, corresponding to about 10% or less viable tumor. The analysis was exploratory and involved neoadjuvant bevacizumab plus chemotherapy. (LLM, conf=0.92)
- Supportedcites [7] Cascone, T. et al. Induction cisplatin docetaxel followed by surgery and erlotinib in non-small cell lung cancer. Ann. Thorac. Surg. 105, 418–424 (2018). source
The Results (Exploratory analysis) report that MPR in the primary tumor after neoadjuvant chemotherapy was significantly associated with superior overall survival. The paper also defines MPR as ≤10% viable tumor cells in resected tumors and describes the patients as having resectable NSCLC. (LLM, conf=0.94)
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In the paper
“An unclassified Ruminococcus sp., a close relative to R. bromii in sequence identity, was associated with MPR in samples from the nivolumab + ipilimumab arm (Extended Data Fig. 8g, bottom panel).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
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In the paper
“LEfSe analysis by treatment arm revealed that Paraprevotella and Akkermansia spp. were associated with MPR in the nivolumab and nivolumab + ipilimumab arms, respectively (Extended Data Fig. 8g).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
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“Tumor and peripheral TCR clonality did not significantly correlate with pathologic tumor regression, despite trends in some cases showing inverse correlation between the two variables (Extended Data Fig. 7c–f), although only a single MPR sample was available for these analyses.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
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“In the resected population of 37 patients, ORRs were 19% in both arms (nivolumab, 4/21 CR/PR (95% CI = 5-42%); nivolumab + ipilimumab, 3/16 CR/PR (95% CI = 4-46%); P = 1.00; Supplementary Table 2).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 37- Asserted: passes — The authors put it forward as true.
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“and no significant differences were noted in the percentage of malignant cells expressing PD-L1 between pre- and post-therapy tumors treated with nivolumab or nivolumab + ipilimumab (Extended Data Fig. 6a).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
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“In an exploratory analysis, tumor specimens resected after nivolumab + ipilimumab contained fewer viable tumor cells as compared with that of nivolumab-treated tumors (P = 0.033; Fig. 1e).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plaincorrelationaln = 37- Asserted: passes — The authors put it forward as true.
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In the paper
“No substantial changes in immune cell subpopulations were detected from pre- to post-therapy in tumors treated with nivolumab alone (Fig. 4f–h, Extended Data Fig. 6),”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
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“Six patients experienced lung cancer-related recurrence (Fig. 2c,d).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 6- Asserted: passes — The authors put it forward as true.
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“We then compared the microbiome composition by arm and at the family level, and found similar distribution of the top ten most abundant bacterial families in patients treated with either nivolumab or nivolumab + ipilimumab.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
plain- Asserted: passes — The authors put it forward as true.
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“Among the five patients who did not undergo surgery, one was treated in the nivolumab arm (4%; 1/23) and four in the nivolumab + ipilimumab arm (19%; 4/21, none related to treatment-related adverse events (TRAEs)).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Surgical resectability.
plainn = 5- Asserted: passes — The authors put it forward as true.
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“Two patients achieved pathologic complete response (pCR) after nivolumab monotherapy (2/23, 9%, 95% CI = 1-28%) compared with six patients treated with nivolumab + ipilimumab (6/21, 29%, 95% CI = 11-52%; P = 0.126; Fig. 1a).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 44- Asserted: passes — The authors put it forward as true.
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“One patient treated with nivolumab developed pneumonia and pneumonitis requiring steroids postoperatively and was diagnosed with bronchopleural fistula (BPF) and empyema, which ultimately resulted in respiratory failure and death. As a result of the sequence of complications, we attributed BPF and death to steroid-treated pneumonitis.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Toxicity.
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“We identified significantly expanded and contracted TCR clones between available pre- and post-therapy samples and determined that the greatest number of clones were expanded and contracted in resected tumors compared with pretherapy blood samples (Extended Data Fig. 7g,h).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
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“Multiplex immunofluorescence (mIF) staining of pre- and post-therapy tumor specimens revealed significant increases from pre- to post-therapy in CD3+ (P = 0.016; Fig. 4e,f) and CD3+CD8+ TILs (P = 0.016; Fig. 4e,g), and a trend toward higher densities of CD3+CD8+CD45RO+ memory TILs (P = 0.078; Fig. 4e,h) in tumors treated with nivolumab + ipilimumab.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The radiographic objective response rate (ORR, partial responses (PRs) plus CR) in the ITT population was 22% (5/23, 95% CI = 7-44%) after nivolumab monotherapy (5 PRs; Fig. 1b), and 19% (4/21, 95% CI = 5-42%) after nivolumab + ipilimumab (1 CR and 3 PRs; one treated patient was not evaluable; P = 1.0; Fig. 1c and Supplementary Table 1).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 44- Asserted: passes — The authors put it forward as true.
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“We observed that a greater proportion of resected tumors had higher TCR richness and clonality compared with their matched tumor-adjacent, uninvolved lung samples (richness, 83.3 % (10/12); clonality, 67% (8/12), respectively; Fig. 5d,e),”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
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“In some cases, we noted radiographic appearance of nodal disease progression with enlargement and/or increased fluorodeoxyglucose (FDG) uptake in nodes at computed tomography (CT) and positron emission tomography (PET)-CT restaging scans, respectively, after neoadjuvant ICIs. However, invasive pathologic examination of the flaring nodes revealed immune cell infiltration changes (noncaseating granu”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
What the sources say
- Not checked yetcites [11] Sepesi, B. et al. Nodal immune flare (NIF) following neoadjuvant anti-PD-1 and anti-CTLA-4 therapy in non-small cell lung cancer. J. Thorac. Oncol. 14, S745–S745 (2019). source
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“Among the 37 patients resected on study, nivolumab monotherapy induced an MPR rate of 24% (5/21, 95% CI = 8-47%), whereas the MPR rate was 50% (8/16, 95% CI = 25-75%) after nivolumab + ipilimumab (P = 0.098; Fig. 1d).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 37- Asserted: passes — The authors put it forward as true.
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“These analyses revealed 1 death among 9 patients with CR/PR (1/9, 11%), and 6 recurrences among 34 patients with SD/PD (6/34, 18%) (Extended Data Fig. 4d).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 34- Asserted: passes — The authors put it forward as true.
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“We also observed an association between Dialister sp. and decreased toxicity to nivolumab and between Bifidobacterium and Enterobacter spp., and an unclassified genus of Erysipelotrochaceae and reduced toxicity to dual therapy (Extended Data Fig. 8h).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“including Akkermansia sp. (R = 0.44, P = 0.05) and Bifidobacterium sp. (R = 0.47, P = 0.04), had a positive correlation with TCR clonality”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
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“In the ITT population of all 44 randomized patients, the primary endpoint of MPR, as assessed by two independent and trained pathologists, was observed in 22% (5/23, 95% confidence interval (CI) = 7-44%) of patients in the nivolumab arm and 38% of patients in the dual therapy arm (8/21, 95% CI = 18-62%; P = 0.235; Fig. 1a).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 44- Asserted: passes — The authors put it forward as true.
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In the paper
“At the last database lock (February 25, 2020), the median duration of follow-up after randomization was 22.2 months. Median OS and lung cancer-related recurrence-free survival (RFS) were not reached.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 44- Asserted: passes — The authors put it forward as true.
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In the paper
“Bacteria associated with T-cell richness included Anaerofustis sp. (R = 0.58, P = 0.001), Faecalibaculum sp. (R = 0.61, P = 0.006), and Ruminococcus_1 sp. (R = −0.65, P = 0.003), among others (Extended Data Fig. 9c,d).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We found a positive association between radiographic tumor responses (CR/PR) and MPR in resected patients (Extended Data Fig. 3). All resected patients with CR/PR (7/7, 95% CI = 59-100%) achieved MPR at surgery, compared with 6 out of 30 (20%, 95% CI = 8-39%) resected patients with stable disease/progressive disease (SD/PD) (P = 0.0002; Supplementary Table 3 and Fig. 1f,g).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plaincorrelationaln = 37- Asserted: passes — The authors put it forward as true.
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In the paper
“Weighted-UniFrac analysis showed similar variability across microbiome communities in both pre- and post-therapy samples, and no difference between both groups of samples (R = −0.032, P = 0.99), or by MPR or TRAE status (Extended Data Fig. 8a,b).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
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“Nine serious adverse events (five treatment related) were noted (Supplementary Table 5).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Toxicity.
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“Blood T-cell richness increased in most samples treated with combination therapy, whereas blood clonality decreased in post-therapy compared with pretherapy blood samples (Extended Data Fig. 7a,b).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The pCR rate was 10% (2/21, 95% CI = 1-30%) after nivolumab alone compared with 38% (6/16, 95% CI = 15-65%) after dual therapy (P = 0.055; Fig. 1d).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Clinical activity of neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 37- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“including Coprococcus_3 sp. (R = −0.48, P = 0.04), Lachnospiraceae_UCG_004 (R = −0.66, P < 0.001) and Lachnospiraceae_unclass (R = −0.47, P = 0.04) were negatively correlated with TCR clonality”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“however, we observed worse lung cancer-related RFS in patients with stage IIIA disease and in never smokers compared with that of patients with stage I/II disease (P = 0.040; Extended Data Fig. 4b), and current/former smokers (P = 0.003; Extended Data Fig. 4c).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plaincorrelationaln = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immune profiling of resected tumor tissues by flow cytometry revealed higher frequencies of CD45+CD3+ tumor-infiltrating lymphocytes (TILs) (P = 0.021; Fig. 4a), CD3+CD4+CD103+ (non-T-regulatory (Treg) tissue-resident memory (TRM) T cells (P = 0.041; Fig. 4b), CD3+CD8+CD103+ effector TRM cells (P = 0.057; Fig. 4c), and CD3+CD4+CD27−CD28+ effector memory T cells (P = 0.034; Fig. 4d)”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Microbiome diversity measured by the inverse Simpson index also appeared to be similar based on MPR status in both the nivolumab (P = 0.301; Extended Data Fig. 8c,d) and the nivolumab + ipilimumab arm (P = 0.336; Extended Data Fig. 8e,f), although these results were derived from a limited number of samples.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Compositional differences in the gut microbiome and their association with treatment response and toxicity.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One patient treated with nivolumab + ipilimumab had PD 2.6 months after randomization (no surgery) (Fig. 2b) and died from the disease 17.1 months after randomization.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumor cell PD-L1 expression by immunohistochemistry (IHC) was overall higher in pretherapy tumor samples from patients who achieved radiographic responses (CR/PR) and MPR compared with that of tumors with SD/PD (P = 0.017; Fig. 3a,e–h) and no MPR (P = 0.037; Fig. 3b,e–h), respectively.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 13 patients with MPR, one death occurred (1/13, 8%), and among 24 patients with no MPR, 3 patients progressed (3/24, 13%) (Extended Data Fig. 4e).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Survival outcomes after neoadjuvant nivolumab and nivolumab + ipilimumab.
plainn = 24- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“T-cell richness and clonality increased from pretherapy to surgery in three out of three tumors treated with dual therapy, but only in two out of four tumors treated with nivolumab (Fig. 5h,i).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Immune responses to neoadjuvant nivolumab and nivolumab + ipilimumab.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Grade 3-5 TRAEs were reported in 13% (3/23) of patients treated with nivolumab (two events occurred in the same patient) and 10% (2/21) of patients treated with nivolumab + ipilimumab (Supplementary Table 4).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Toxicity.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although we found overall higher tumor PD-L1 expression in baseline samples from responding patients, we also observed responses in patients lacking pretreatment tumor PD-L1.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed enhanced T-cell infiltration in tumors treated with combination therapy; however, immune cell infiltration of tumors was independent of MPR.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NIF is characterized by the radiographic appearance of disease progression in lymph nodes that were histologically negative at baseline and that became enlarged and/or FDG avid after neoadjuvant ICIs.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the present study, nivolumab monotherapy produced an MPR of 22% in 23 treated patients and 24% in 21 resected tumors.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plaindirectn = 23- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The higher TCR richness and clonality in a greater proportion of treated tumors as compared to tumor-adjacent, uninvolved lung samples indicate that resected tumors may have a more diverse T-cell repertoire after neoadjuvant immune checkpoint blockade, with a subset of dominant clones accounting for the higher clonality, although these results were irrespective of response.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among four resected patients who received PORT (4/37, 11%), two patients (2/4, 50%) progressed, and among 33 resected patients who did not receive PORT (33/37, 89%), two patients (2/33, 6%) progressed/died.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 13 resected patients with MPR (13/37, 35%), one patient (1/13, 8%) died 2.2 months after surgery, and among 24 resected patients with no MPR (24/37, 65%), three (3/24, 13%) patients progressed 15.0, 16.4, and 17.9 months after surgery.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainn = 24- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 26 patients with adenocarcinoma (26/44, 59%), four patients (4/26, 15%) progressed, and among 18 patients with SCC/ASC (18/44, 41%), three patients (3/18, 17%) progressed/died.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainn = 26- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One patient developed TRAE (SAE) after one dose of nivolumab plus ipilimumab and RECIST response and percent change in tumor size from baseline were not evaluable.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 36 former/current smokers (36/44, 82%), three patients (3/36, 8%) progressed, and among eight never smokers (8/44, 18%), four patients (4/8, 50%) progressed/died.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 23 patients with stage I disease (23/44, 52%), one patient (1/23, 4%) progressed, among 12 patients with stage II disease (12/44, 27%), two patients (2/12, 17%) progressed/died, and among nine patients with stage IIIA disease (9/44, 20%), four patients (4/9, 44%) progressed.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainn = 23- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In one patient, the solid lesion was <1 cm following three doses of nivolumab monotherapy and did not change compared to baseline; response was considered SD.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 17 resected patients who received adjuvant chemotherapy (17/37, 46%), two patients (2/17, 12%) progressed, and among 20 resected patients who did not receive adjuvant chemotherapy (20/37, 54%), two patients (2/20, 10%) progressed/died.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plainn = 17- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, 41 (93%) patients completed the planned neoadjuvant therapy regimen (nivolumab arm 22 (96%), dual therapy 19 (90%)).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Participants.
plainn = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“First-line nivolumab + ipilimumab treatment also produced longer OS than chemotherapy in patients with advanced NSCLC10.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Introduction
What the sources say
- Not checked yetcites [10] Hellmann, M. D. et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“44 eligible patients were treated on the study, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab + ipilimumab”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Results > Participants.
plainn = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Perioperative (neoadjuvant or adjuvant) chemotherapy provides only a modest (approximately 5%) improvement in 5-year overall survival (OS) and is a source of toxicity2,3,”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Introduction
What the sources say
- Not checked yetcites [2] Pignon, J. P. et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J. Clin. Oncol. 26, 3552–3559 (2008). source
- Not checked yetcites [3] Group, N. M.-A. C. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 383, 1561–1571 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the 95% CI of the MPR rate to neoadjuvant nivolumab + ipilimumab was relatively wide (18-62%), which indicates that further studies with a larger sample size could more precisely determine the magnitude of increment of the primary endpoint compared with chemotherapy alone.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Amaria and colleagues17 demonstrated that a more clonal T-cell repertoire at baseline correlated with response to neoadjuvant ICI therapy in patients with melanoma, with further expansion of the pre-existing high-frequency clones with treatment.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [17] Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In contrast, in studies performed in patients with treatment-naïve and resected NSCLC, higher TCR clonality was observed in the uninvolved resected lung22.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [22] Reuben, A. et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nat. Commun. 11, 603 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, the extent of pathologic response in some tumors rendered them unavailable for analysis and the longer duration between ipilimumab dosing and surgery may not have coincided with the maximal immune cell response.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The toxicity profile was overall manageable with no new safety concerns.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Previous studies demonstrated that enhanced CD8+CD103+ TRM TILs correlate with improved survival in patients with early stage NSCLC18 and with other types of cancer19.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [18] Djenidi, F. et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015). source
- Not checked yetcites [19] Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Studies in melanoma using higher dosages of ipilimumab reported enhanced immune infiltration in responding tumors17.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [17] Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Recent studies have shown that higher diversity and relative abundance of fecal Ruminococcaceae are associated with response to ICIs in patients with melanoma26.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [26] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of ipilimumab to nivolumab produced twice as many MPRs in resected patients compared to nivolumab alone (50% versus 24%) and a greater proportion of pCRs compared with nivolumab (38% versus 10%).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Wei and colleagues20 have shown that combination therapy with CTLA-4 and PD-1 blockade mediates a switch from expansion of exhausted CD8+ T cells to expansion of activated effector CD8+ T cells.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [20] Wei, S. C. et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc. Natl Acad. Sci. USA 116, 22699–22709 (2019). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Studies in other cancers suggest that peripheral T-cell expansion to adjacent uninvolved tissues and tumors is a key determinant of clinical benefit from immunotherapy23.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [23] Wu, T. D. et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 579, 274–278 (2020). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The expansion of T-cell clones from the periphery to the resected tumors may represent a recruitment of dominant clones after neoadjuvant therapy; however, further studies are needed in larger sets of samples.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“We have previously shown that the histopathologic response to neoadjuvant chemotherapy is a stronger predictor of improved survival outcome, compared with responses at CT13,25.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [13] Cascone, T. et al. A Phase I/II study of neoadjuvant cisplatin, docetaxel and nintedanib for resectable non-small cell lung cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-4180 (2020). source
- Not checked yetcites [25] William, W. N. Jr et al. Computed tomography RECIST assessment of histopathologic response and prediction of survival in patients with resectable non-small-cell lung cancer after neoadjuvant chemotherapy. J. Thorac. Oncol. 8, 222–228 (2013). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments and scorings related to the presented results were conducted once.”
- Also stated in: § Extended Data · plain
“Experiments and scorings related to the presented results were conducted once.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Extended Data · plain
In the paper
“We applied a Bayesian method to formally monitor the toxicity in the perioperative phase within each treatment arm32.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Sample size justification and toxicity monitoring guidelines.
What the sources say
- Not checked yetcites [32] Thall, P. F., Simon, R. M. & Estey, E. H. New statistical strategy for monitoring safety and efficacy in single-arm clinical trials. J. Clin. Oncol. 14, 296–303 (1996). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Subgating was only performed when more than 100 events were present in parental gate.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No blinding was done as part of this study.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Interventions.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The study was approved by the University of Texas MD Anderson Cancer Center’s Institutional Review Board.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Study oversight, ethical approval and ethical standards.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“It was not powered to formally test the differences in clinical activity and immune responses between the two treatment arms, but rather to compare tumor responses in both arms with historical controls of neoadjuvant chemotherapy.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments and gating related to the presented results were conducted once.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Multiparameter flow cytometry.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“To maximize interobserver consistency, these two pathologists had undergone an initial training period consisting of co-examination of 5-10 slide samples followed by examining 5-10 slide samples independently, with subsequent review and consensus agreement on tumor response12.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Pathologic assessment.
What the sources say
- Not checked yetcites [12] Weissferdt, A. et al. Agreement on major pathological response in nsclc patients receiving neoadjuvant chemotherapy. Clin. Lung Cancer https://doi.org/10.1016/j.cllc.2019.11.003 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, our findings provide evidence that the addition of neoadjuvant ipilimumab to nivolumab produces higher rates of MPR and pCR and enhances tumor immune infiltrates and immunologic memory.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The Data and Safety Monitoring Board provided oversight until all participants randomized to arms A (nivolumab) and B (nivolumab + ipilimumab) completed treatment on study.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Study oversight, ethical approval and ethical standards.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The randomization was performed by the clinical trial coordinator using the database system in the Department of Biostatistics by applying the Pocock Simon minimization method with stage as a stratification factor.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Interventions.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Building on these results, and on the recent findings of the CheckMate 9LA study, showing that in patients with advanced NSCLC front-line nivolumab + ipilimumab combined with chemotherapy improved survival compared with chemotherapy alone30, our study sets the stage to evaluate the role of dual ICIs added to neoadjuvant chemotherapy, which is currently being tested (NCT03158129).”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [30] Reck, M. et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J. Clin. Oncol. 38, 9501–9501 (2020). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments and scorings related to the presented micrographs were conducted once.”
- Also stated in: § IHC of PD-L1 and analysis. · plain
“Experiments and scorings related to the presented micrographs were conducted once.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > MIF staining and analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § IHC of PD-L1 and analysis. · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After initial clinical reporting, pathologic responses were subsequently reviewed in a blinded manner by two pathologists experienced in the evaluation of tumor response after neoadjuvant therapy, and the average scores were used for final analysis.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Pathologic assessment.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Written informed consent was provided by all study participants or their legal representatives.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Study oversight, ethical approval and ethical standards.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The prespecified boundary for a treatment arm to be considered promising for further testing was ≥6 MPRs in 21 evaluable patients.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Trial design, hypotheses and endpoints.
plainn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Subsequent analyses comparing the two treatments arms are considered to be exploratory in nature.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Statistical methods.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When the MPR rate is 15%, the probability of early termination is 60%, with an average sample size of 17.4 and one-sided 10% type I error rate.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Methods > Sample size justification and toxicity monitoring guidelines.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of pre- and post-therapy samples and the number of tissues derived from resected tumors with MPR for correlatives was limited.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The results of the reported comparisons are exploratory and hypothesis generating, including the findings of our gut microbiome qualitative and correlative analyses, and require additional investigations, such as validation of proposed biomarker bacteria with quantitative measurements and deeper taxonomic and functional characterization.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Similarly, Akkermansia muciniphila was associated with favorable clinical outcomes in patients with melanoma, NSCLC and renal cell carcinoma receiving ICIs in previous studies26,27.”
§ Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial > Discussion
What the sources say
- Not checked yetcites [26] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). source
- Not checked yetcites [27] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The efficacy and impact of ipilimumab on the immune microenvironment in operable NSCLC were unclear before this study.
“Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear.”
The paper relies on this without support.
The impact of dual ICI therapy on the immune microenvironment of resectable NSCLC had not been established.
“Although the addition of ipilimumab to nivolumab therapy has dramatically altered care of patients with advanced NSCLC, the impact of this dual ICI therapy on the immune microenvironment of resectable NSCLC has not been established.”
The paper relies on this without support.
NEOSTAR is the first reported randomized phase 2 trial testing neoadjuvant nivolumab and nivolumab plus ipilimumab in resectable NSCLC using MPR as the primary endpoint.
“NEOSTAR is the first reported, randomized phase 2 trial testing neoadjuvant nivolumab and nivolumab + ipilimumab in patients with resectable NSCLC using MPR as the primary endpoint.”
The authors state this as an assumption.
This is the first report of neoadjuvant ICIs imparting immunologic memory in clinical specimens of resected NSCLC.
“To our knowledge, this is the first report of neoadjuvant ICIs imparting immunologic memory in clinical specimens of resected NSCLC.”
The paper relies on this without support.
This trial is the first completed randomized study to compare neoadjuvant nivolumab alone with nivolumab plus ipilimumab in resectable NSCLC.
“Despite these limitations, to our knowledge, this is the first completed randomized study comparing the impact of neoadjuvant nivolumab monotherapy and combined nivolumab + ipilimumab in resectable NSCLC.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Over the past decade, following the epidemiological demonstration of the negative effect of antibiotics on the efficacy of ICIs13,42,90, specific microbial taxa have been associated with response or resistance to ICIs across distinct cancer types26,38–40,42,91–100.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [93]
Citations
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“50%), and greater frequencies of effector, tissue-resident memory and effector memory T cells compared to nivolumab alone [136].”
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Self-citationNeoadjuvant immune checkpoint blockade: A window of opportunity to advance cancer immunotherapy
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“One recent trial evaluating 6 weeks of neoadjuvant nivolumab and ipilimumab treatment was terminated early after inclusion of nine patients only because of a high rate of treatment-related AEs grade $ 3 and 3 patients with biopsy-confirmed tumor progression precluding surgery,(29) whereas in the NEOSTAR trial, 17 of 2…”
ResultImmune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Progress, Challenges, and Prospects
Tang, S., Qin, C., Hu, H., Liu, T., He, Y., Guo, H., Yan, H., Zhang, J., Tang, S., & Zhou, H. (2022) · Cells · doi:10.3390/cells11030320 · Cited by 273
“This phase II randomized study indicates that neoadjuvant nivolumab plus ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates, and immunologic memory, thus meriting further investigation for used in cases of operable NSCLC [61].”
BackgroundSelf-citationMino-Kenudson, M. A., Schalper, K. A., Cooper, W. A., Đačić, S., Hirsch, F. R., Jain, D., López‐Ríos, F., Tsao, M., Yatabe, Y., Beasley, M. B., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.09.109 · Cited by 240
“Published studies in chemotherapy and chemoradiotherapy revealed prognostic significance of MPR with a cutoff of 10% or less viable tumor.138,139,150,151 More recent studies suggested the best cutoff of 10% viable tumor for squamous cell carcinoma and that of 65% for adenocarcinoma.140,152,153 Preliminary data suggest…”
BackgroundSelf-citationHu, H., Kang, L., Zhang, J., Wu, Z., Wang, H., Huang, M., Lan, P., Wu, X., Wang, C., Cao, W., et al. (2021) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(21)00348-4 · Cited by 314
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Self-citationOverall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer
Forde, P. M., Spicer, J. D., Provencio, M., Mitsudomi, T., Awad, M. M., Wang, C., Lu, S., Felip, E., Swanson, S., Brahmer, J. R., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2502931 · Cited by 273
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Mountzios, G., Remón, J., Hendriks, L. E. L., García‐Campelo, R., Rolfo, C. D., Schil, P. E. V., Forde, P. M., Besse, B., Subbiah, V., Reck, M., et al. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00794-7 · Cited by 212
Advances in molecular pathology and therapy of non-small cell lung cancer
Huang, Q., Li, Y., Huang, Y., Wu, J., Bao, W., Xue, C., Li, X., Dong, S., Dong, Z., & Hu, S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02243-6 · Cited by 197
Revisiting neoadjuvant therapy in non-small-cell lung cancer
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“In NSCLC patients, compared with neoadjuvant nivolumab, the combination therapy of nivolumab and ipilimumab can signi fi cantly improve the pathological complete response rates, tumor immune in fi ltrates and immune memory effects [73].”
ResultModulating gut microbiome in cancer immunotherapy: Harnessing microbes to enhance treatment efficacy
Kang, X., Lau, H. C.-H., & Yu, J. Q. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101478 · Cited by 172
Management of locally advanced non‐small cell lung cancer: State of the art and future directions
Miao, D., Zhao, J., Han, Y., Zhou, J., Li, X., Zhang, T., Li, W., & Xia, Y. (2023) · 癌症：英文版 · doi:10.1002/cac2.12505 · Cited by 165
“1) [78].”
Preoperative and Postoperative Systemic Therapy for Operable Non–Small-Cell Lung Cancer
Chaft, J. E., Shyr, Y., Sepesi, B., & Forde, P. M. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.01589 · Cited by 224
Self-citationGut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy
Thomas, A. M., Fidelle, M., Routy, B., Kroemer, G., Wargo, J. A., Segata, N., & Zitvogel, L. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00785-8 · Cited by 141
Self-citationCascone, T., Kar, G., Spicer, J. D., García-Campelo, R., Weder, W., Daniel, D. B., Spigel, D. R., Hussein, M., Mazières, J., Oliveira, J., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0436 · Cited by 142
“In the intent-to-treat (ITT) population of the NEOSTAR trial, 38% and 22% of patients had an MPR in the combination and monotherapy arms, respectively, whereas 29% and 9% had a pCR, respectively (5); the rate of grade 3 or higher TRAEs was 10% in the combination arm.”
Self-citationSomaiah, N., Conley, A. P., Parra, E. R., Lin, H., Amini, B., Solis Soto, L., Salazar, R., Barreto, C., Chen, H., Gite, S., et al. (2022) · The Lancet Oncology · doi:10.1016/s1470-2045(22)00392-8 · Cited by 159
Self-citationVerschoor, Y. L., van de Haar, J., van den Berg, J. G., van Sandick, J. W., Kodach, L. L., van Dieren, J. M., Balduzzi, S., Grootscholten, C., Ijsselsteijn, M. E., Veenhof, A. A. F. A., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02758-x · Cited by 135
“These data are in line with the previously described underestimation of response to (neoadjuvant) immunotherapy by radiographic assessment across tumor types, highlighting the need for more accurate methods of response evaluation 17,29–31 .”
ResultLocalization, tissue biology and T cell state — implications for cancer immunotherapy
Schenkel, J. M., & Pauken, K. E. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00884-8 · Cited by 144
Cascone, T., Weissferdt, A., Godoy, M. C. B., William, W. N., Leung, C. H., Lin, H. Y., Basu, S., Yadav, S. S., Pataer, A., Mitchell, K. G., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25188-0 · Cited by 107
Self-citationStage III Non-Small-Cell Lung Cancer: An Overview of Treatment Options
Petrella, F., Rizzo, S., Attili, I., Passaro, A., Zilli, T., Martucci, F., Bonomo, L. D., Grande, F. D., Casiraghi, M., de Marinis, F., et al. (2023) · Current Oncology · doi:10.3390/curroncol30030239 · Cited by 112
“The results of these trials showed that the ICI treatment had no adverse effects on surgical outcomes, with previously unreported response rates ranging from 14–45% and a pathological complete response (pCR) up to 16% with single agent anti-PD-1/PD-L1 [70,71].”
BackgroundResultHeymach, J. V., Mitsudomi, T., Harpole, D. H., Aperghis, M., Jones, S., Mann, H., Fouad, T. M., & Reck, M. (2021) · Clinical Lung Cancer · doi:10.1016/j.cllc.2021.09.010 · Cited by 123
Self-citationImmunotherapy in non-small cell lung cancer: Past, present, and future directions
Punekar, S. R., Shum, E., Grello, C., Lau, S. C. M., & Velcheti, V. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.877594 · Cited by 89
Updated Prognostic Factors in Localized NSCLC
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Exploiting temporal aspects of cancer immunotherapy
Zemek, R. M., Anagnostou, V., da Silva, I. P., Long, G. V., & Lesterhuis, W. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00699-2 · Cited by 96
“Taking NSCLC as a representative example of an ICT-responsive tumour, ctDNA clearance on week 6 after anti-PD1 signifies a molecular response that may be more informative than radiographic imaging in predicting long-term clinical outcomes 72 .”
InfluentialConditioning of the immune system by the microbiome
Graham, D. B., & Xavier, R. J. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.05.002 · Cited by 103
Terrisse, S., Goubet, A.-G., Ueda, K., Thomas, A. M., Quiniou, V., Thelemaque, C., Dunsmore, G., Clave, E., Gamat-Huber, M., Yonekura, S., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004191 · Cited by 80
Tumour and microenvironment crosstalk in NSCLC progression and response to therapy
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Nederlof, I., Isaeva, O. I., de Graaf, M., Gielen, R., Bakker, N. A. M., Rolfes, A. L., Garner, H., Boeckx, B., Traets, J. J. H., Mandjes, I. A. M., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03249-3 · Cited by 88
“MPR (the secondary end point) is a frequently used surrogate end point for efficacy in neoadjuvant trials evaluating immune checkpoint blockade across cancer types 8,11,26 .”
Neoadjuvant Targeted Therapy in Resectable NSCLC: Current and Future Perspectives
Lee, J. M., McNamee, C., Toloza, E. M., Negrao, M. V., Lin, J., Shum, E., Cummings, A. L., Kris, M. G., Sepesi, B., Bāra, I., et al. (2023) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2023.07.006 · Cited by 89
Self-citationImmune-based therapies in penile cancer
Joshi, V. B., Spiess, P. E., Necchi, A., Pettaway, C. A., & Chahoud, J. (2022) · Nature Reviews Urology · doi:10.1038/s41585-022-00617-x · Cited by 66
Pulmonary toxicity of immune checkpoint immunotherapy
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“Investigational ICIs included PD-1/ PD-L1 inhibitors such as nivolumab (13,18,25,27,28), pembrolizumab (16,20), sintilimab (15), durvalumab (26), atezolizumab (14,19), avelumab (23), and a CTLA-4 inhibitor ipilimumab (24).”
BackgroundLiu, C., Zhao, W., Xie, J., Lin, H., Hu, X., Li, C., Shang, Y., Wang, Y., Jiang, Y., Ding, M.-G., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1115291 · Cited by 76
Self-citationNeoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?
Ahern, E. S., Solomon, B., Hui, R., Pavlakis, N., O'Byrne, K. J., & Hughes, B. G. M. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002248 · Cited by 65
Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy
Gu, Y., Zhang, Z., & ten Dijke, P. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-00980-8 · Cited by 78
Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial
Davar, D., Morrison, R. M., Dzutsev, A., Karunamurthy, A. D., Chauvin, J.-M., Amatore, F., Deutsch, J. S., das Neves, R. X., Rodrigues, R. R., McCulloch, J. A., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.10.007 · Cited by 75
Current Surgical Indications for Non-Small-Cell Lung Cancer
Deboever, N., Mitchell, K. G., Feldman, H. A., Cascone, T., & Sepesi, B. (2022) · Cancers · doi:10.3390/cancers14051263 · Cited by 60
“The NEOSTAR phase 2 randomized trial showed that neoadjuvant nivolumab plus ipilimumab, a CTLA-4 inhibitor, was promising for further testing as compared to historical controls of neoadjuvant platinum-based chemotherapy in patients with resectable NSCLC, as determined by major pathological response [51].”
BackgroundInfluentialSelf-citationRoland, C. L., Nassif, E. F., Keung, E. Z.-Y., Wang, W., Lazar, A. J., Lin, H. Y., Chelvanambi, M., Parra, E. R., Wani, K., Guadagnolo, B. A., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00726-z · Cited by 64
Self-citationFive-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non–Small Cell Lung Cancer
Rosner, S., Reuss, J. E., ZAHURAK, M. L., Zhang, J., Zeng, Z., Taube, J. M., Anagnostou, V., Smith, K. N., Riemer, J., Illei, P. B., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2994 · Cited by 75
“Subsequent studies, incorporating neoadjuvant dual-ICB and chemoimmunotherapy have shown improvement in pathological response based on pretreatment PD-L1 positivity (5, 19, 20).”
BackgroundSelf-citationGut microbiome for predicting immune checkpoint blockade-associated adverse events
Hu, M., Lin, X., Sun, T., Shao, X., Huang, X., Du, W., Guo, M., Zhu, X., Zhou, Y., Tong, T., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01285-9 · Cited by 72
“…Read Archive (SRA) using the following identifiers: PRJNA665109 (https:// www. ncbi. nlm. nih. gov/ biopr oject/ PRJNA 665109) for Cascone et al. [30], PRJNA687361 (https:// www. ncbi. nlm. nih. gov/ biopr oject/ PRJNA 687361) for Chau et al. [31], PRJNA606061 (https:// www. ncbi. nlm. nih. gov/…”
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“The addition of ipilimumab to nivolumab led to a 50% MPR rate in one study.(27) Regarding the combination of chemoradiotherapy with durvalumab, MPR rate was reported to be 73%.”
BackgroundInfluentialLee, Y. J., Kim, J. Y., Jeon, S. H., Nam, H., Jung, J. H., Jeon, M., Kim, E.-S., Bae, S. J., Ahn, J., Yoo, T.-K., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn8390 · Cited by 56
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“Distant recurrence 1 (4) 85 (1) 1 (4) 85 (1)”
InfluentialPerioperative Systemic Therapy for Resectable Non–Small Cell Lung Cancer
Muthusamy, B., Patil, P. D., & Pennell, N. A. (2022) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2022.7021 · Cited by 69
Perioperative Immune Checkpoint Inhibition in Early-Stage Non–Small Cell Lung Cancer
Desai, A. P., Adashek, J. J., Reuss, J. E., West, H., & Mansfield, A. S. (2022) · JAMA Oncology · doi:10.1001/jamaoncol.2022.5389 · Cited by 51
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Neoadjuvant Immunotherapy: Leveraging the Immune System to Treat Early-Stage Disease
Mittendorf, E. A., Burgers, F. H., Haanen, J. B. A. G., & Cascone, T. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_349411 · Cited by 54
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“Ipilimumab plus nivolumab increased the frequency of CD3+, CD3+CD8+, and CD3+CD8+CD45RO+ memory TILs in post-operative tumor samples compared to preoperative samples, whereas nivolumab monotherapy had no effect [125].”
ResultMechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer
Zhou, K., Li, S., Zhao, Y., & Cheng, K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1127071 · Cited by 49
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Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives
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“NEOSTAR was a phase II trial comparing the efficacy of nivolumab to nivolumab + ipilimumab in 44 resectable NSCLC patients with stage IA-IIIA cancers [17].”
MethodCombination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer – a brief update
Park, J., & Skålhegg, B. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1680838 · Cited by 66
“%) and pathological complete response (pCR: 38% vs 10%), along with enhanced immune in fi ltration and memory (118).”
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“Compared with nivolumab monotherapy, nivolumab plus ipilimumab resulted in higher pCR rates (10% versus 38%), less viable tumor (median 50% versus 9%), higher MPR (50% versus 24%), and greater frequencies of effector, tissue-resident memory T cells [66].”
BackgroundXie, Y., Lin, J., Zhang, N., Wang, X., Wang, P., Peng, S., Li, J., Wu, Y., Huang, Y., Zhuang, Z., et al. (2023) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2022.7071 · Cited by 49
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Challenges and controversies in resectable non-small cell lung cancer: a clinician’s perspective
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“51 Improvements in diagnosis is also universally important.”
BackgroundCharting roadmaps towards novel and safe synergistic immunotherapy combinations
Sanmamed, M. F., Berraondo, P., Rodriguez-Ruiz, M. E., & Melero, I. (2022) · Nature Cancer · doi:10.1038/s43018-022-00401-1 · Cited by 50
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“[107].”
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“Further improvements in outcomes associated with immune checkpoint blockade may be accomplished by dual checkpoint inhibition 13,14 or by combining immune checkpoint blockade with potentially immuno-modulating agents such as low-dose or metronomic chemotherapy, targeted anticancer agents, or…”
Zhang, Y., Cheng, S., Zou, H., Han, Z., Xie, T., Zhang, B., Dai, D., Yin, X., Liang, Y., Kou, Y., et al. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1099063 · Cited by 42
Wu, Y., Verma, V., Gay, C. M., Chen, Y., Liang, F., Lin, Q., Wang, J., Zhang, W., Hui, Z., Zhao, M., et al. (2023) · Cancer · doi:10.1002/cncr.34755 · Cited by 37
Houda, I., Dickhoff, C., Groot, C. A. U., Reguart, N., Provencio, M., Lévy, A., Dziadziuszko, R., Pompili, C., Maïo, M. D., Thomas, M., et al. (2024) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2024.100840 · Cited by 36
The rapidly evolving paradigm of neoadjuvant immunotherapy across cancer types
Awada, G., Cascone, T., van der Heijden, M. S., Blank, C. U., Kok, M., & Chalabi, M. (2025) · Nature Cancer · doi:10.1038/s43018-025-00990-7 · Cited by 51
“In the phase 2 NEOSTAR platform study, nivolumab alone or combined with ipilimumab in resectable stage I–IIIA NSCLC produced MPR rates of 22% and 38% and pCR rates of 9% and 29%, respectively 70 .”
Self-citationNeoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer
Awad, M. M., Forde, P. M., Girard, N., Spicer, J. D., Wang, C., Lü, S., Mitsudomi, T., Felip, E., Broderick, S., Swanson, S., et al. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-24-02239 · Cited by 47
Chen, Y., Qin, J., Wu, Y., Lin, Q., Wang, J., Zhang, W., Liang, F., Hui, Z., Zhao, M., & Wang, J. (2023) · International Journal of Surgery · doi:10.1097/js9.0000000000000496 · Cited by 43
“It Forde PM et al, 2022 [9] randomised, Cascone,T.etal,2021 [14] randomized,phaseII Huang Z et al, 2021 [24] Retrospective [28] prospective,single-arm 44 [32] prospective,single-arm 72 [33] prospective,single-arm 23 [35] prospective,single-arm 13 [37] prospective,single-arm 22 [39]…”
InfluentialNeoadjuvant Chemotherapy Plus Immunotherapy in Early-Stage Resectable Non–Small-Cell Lung Cancer
Passaro, A., Attili, I., & de Marinis, F. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.22.00873 · Cited by 52
Role and impact of immune checkpoint inhibitors in neoadjuvant treatment for NSCLC
Friedlaender, A., Naidoo, J., Banna, G. L., Metro, G., Forde, P. M., & Addeo, A. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102350 · Cited by 38
Govindan, R., Aggarwal, C., Antonia, S. J., Davies, M. J., Dubinett, S. M., Ferris, A. A., Forde, P. M., Garon, E. B., Goldberg, S. B., Hassan, R., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003956 · Cited by 46
“141 Another atypical pattern of response occasionally observed with ICI treatment is hyperprogression, where a profound increase in tumor growth rate is seen after therapy.”
Self-citationSzeto, C. H., Shalata, W., Yakobson, A., & Agbarya, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10235614 · Cited by 41
“Both studies showed improved pCR rate on the nivolumab plus ipilimumab arm compared to the nivolumab arm [15,19].”
MethodResultSaqi, A., Leslie, K. O., Moreira, A. L., Lantuéjoul, S., Shu, C. A., Rizvi, N. A., Sonett, J. R., Tajima, K., Sun, S. W., Gitlitz, B. J., et al. (2022) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2022.100310 · Cited by 29
“…specimen and all sampled regional lymph nodes Efficacy of neoadjuvant nivolumab ± ipilimumab in patients with stages I–IIIA resectable NSCLC (NEOSTAR) (Cascone et al, 2021)11 37 patients who had surgery on study After gross identification of tumor/ tumor bed, 1 section per centimeter of greatest…”
MethodImmune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer
Parra, E. R., Zhang, J., Jiang, M., Tamegnon, A., Pandurengan, R. K., Behrens, C., Solis, L. M., Haymaker, C., Heymach, J. V., Moran, C. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37905-y · Cited by 47
Self-citationHasegawa, H., Shitara, K., Takiguchi, S., Takiguchi, N., Ito, S., Kochi, M., Horinouchi, H., Kinoshita, T., Yoshikawa, T., Muro, K., et al. (2022) · Gastric Cancer · doi:10.1007/s10120-022-01286-w · Cited by 37
“Patients with resectable GC received 2 doses of intravenous nivolumab at a dose of 240 mg/body every 2 weeks, which is the same as the previous trial for NSCLC [14].”
BackgroundInfluentialZhou, C., Qin, Y., Zhao, W. M., Liang, Z., Li, M., Liu, D., Bai, L., Chen, Y., Chen, Y., Cheng, Y. S., et al. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-23-339 · Cited by 39
“Two prospective studies (192,193) on the changes in lung function after the use of ICIs in patients with LC-COPD consistently showed that neoadjuvant immunotherapy for NSCLC did not worsen lung function; rather, FEV 1 , FVC%, and DLCO were improved after the treatment.”
Self-citationReijers, I. L. M., Menzies, A. M., López‐Yurda, M., Versluis, J. M., Rozeman, E. A., Saw, R. P. M., van Houdt, W. J., Kapiteijn, E., van der Veldt, A. A. M., Suijkerbuijk, K. P. M., et al. (2024) · European Journal of Cancer · doi:10.1016/j.ejca.2024.115141 · Cited by 35
Neoadjuvant immunotherapy of locoregionally advanced solid tumors
Tarhini, A. A., Eads, J. R., Moore, K. N., Tatard-Leitman, V. M., Wright, J., Forde, P. M., & Ferris, R. L. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005036 · Cited by 40
Neoadjuvant therapy in non-small cell lung cancer
Grant, C., Hagopian, G. G., & Nagasaka, M. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104080 · Cited by 47
Neoadjuvant therapy in non-small cell lung cancer: basis, promise, and challenges
Kalvapudi, S., Vedire, Y., Yendamuri, S., & Barbi, J. J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1286104 · Cited by 30
Metadata
- Authors
- Cascone, T., William, W. N., Weissferdt, A., Leung, C. H., Lin, H. Y., Pataer, A., Godoy, M. C. B., Carter, B. W., Federico, L., Reuben, A., Khan, M. A. W., Dejima, H., Francisco-Cruz, A., Parra, E. R., Solis, L. M., Fujimoto, J., Tran, H. T., Kalhor, N., Fossella, F. V., Mott, F. E., Tsao, A. S., Blumenschein, G., Le, X., Zhang, J., Skoulidis, F., Kurie, J. M., Altan, M., Lu, C., Glisson, B. S., Byers, L. A., Elamin, Y. Y., Mehran, R. J., Rice, D. C., Walsh, G. L., Hofstetter, W. L., Roth, J. A., Antonoff, M. B., Kadara, H., Haymaker, C., Bernatchez, C., Ajami, N. J., Jenq, R. R., Sharma, P., Allison, J. P., Futreal, A., Wargo, J. A., Wistuba, I. I., Swisher, S. G., Lee, J. J., Gibbons, D. L., Vaporciyan, A. A., Heymach, J. V., & Sepesi, B.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Cascone, Tina
- ORCID
- Cascone, Tina
- William, William N.
- Weissferdt, Annikka
- Leung, Cheuk H.
- Lin, Heather Y.
- Pataer, Apar
- Carter, Brett W.
- Federico, Lorenzo
- Reuben, Alexandre
- Khan, Md Abdul Wadud
- Dejima, Hitoshi
- Parra, Edwin R.
- Solis, Luisa M.
- Fujimoto, Junya
- Tran, Hai T.
- Kalhor, Neda
- Mott, Frank E.
- Tsao, Anne S.
- Le, Xiuning
- Zhang, Jianjun
- Skoulidis, Ferdinandos
- Kurie, Jonathan M.
- Altan, Mehmet
- Lu, Charles
- Glisson, Bonnie S.
- Byers, Lauren Averett
- Elamin, Yasir Y.
- Mehran, Reza J.
- Rice, David C.
- Hofstetter, Wayne L.
- Roth, Jack A.
- Antonoff, Mara B.
- Kadara, Humam
- Haymaker, Cara
- Bernatchez, Chantale
- Ajami, Nadim J.
- Jenq, Robert R.
- Sharma, Padmanee
- Allison, James P.
- Futreal, Andrew
- Wargo, Jennifer A.
- Wistuba, Ignacio I.
- Swisher, Stephen G.
- Lee, J. Jack
- Gibbons, Don L.
- Vaporciyan, Ara A.
- Heymach, John V.
- Sepesi, Boris
- Venue
- Nature Medicine
- Published
- 2021-02-18
- Volume
- 27
- Issue
- 3
- Pages
- 504-514
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC8818318
- OpenAlex
- W3132841322
- Cited by
- 618
- References
- 46
- Citations by year
- 2026: 54 · 2025: 92 · 2024: 124 · 2023: 160 · 2022: 141 · 2021: 47
- FWCI
- 42.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA070907, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- neoadjuvant immunotherapy, nivolumab, ipilimumab, major pathological response, tumor immune microenvironment, T cell memory, gut microbiota, Ruminococcus, Akkermansia, tumor immune infiltrate
- MeSH terms
- Ipilimumab, Nivolumab, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Biomarkers, Tumor, Neoadjuvant Therapy
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