Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial

May combine two claims.

Among five patients who did not undergo surgery, one was in the nivolumab arm (4%; 1/23) and four in the dual arm (19%; 4/21), none related to treatment-related adverse events.

“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)).”

May combine two claims.

In the intention-to-treat population, pCR occurred in 9% (2/23) of the nivolumab arm and 29% (6/21) of the dual arm, with P=0.126.

“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).”

May combine two claims.

One nivolumab patient developed postoperative pneumonia and pneumonitis requiring steroids, bronchopleural fistula and empyema, respiratory failure and death; the fistula and death were attributed to steroid-treated pneumonitis.

“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.”

May combine two claims.

Significantly expanded and contracted TCR clones were identified between pre- and post-therapy samples, with the greatest number in resected tumors compared with pretherapy blood.

“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).”

May combine two claims.

In dual-treated tumors, multiplex immunofluorescence showed significant increases from pre- to post-therapy in CD3+ (P=0.016) and CD3+CD8+ TILs (P=0.016), and a trend toward higher CD3+CD8+CD45RO+ memory TILs (P=0.078).

“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.”

May combine two claims.

In the intention-to-treat population, ORR was 22% (5/23) for nivolumab and 19% (4/21) for dual therapy, with P=1.0.

“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).”

May combine two claims.

A greater proportion of resected tumors had higher TCR richness (83.3%, 10/12) and clonality (67%, 8/12) compared with matched tumor-adjacent uninvolved lung.

“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),”

May combine two claims.

Nodal immune flare occurred after neoadjuvant ICIs: radiographic nodal progression but pathologic examination showed immune cell infiltration with noncaseating granulomas, not malignancy.

“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”

• cites [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). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Among 37 patients resected on study, MPR rate was 24% (5/21) for nivolumab and 50% (8/16) for dual therapy, with P=0.098.

“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).”

May combine two claims.

Exploratory landmark analyses showed 1 death among 9 CR/PR patients (11%) and 6 recurrences among 34 SD/PD patients (18%).

“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).”

May combine two claims.

Dialister sp. was associated with decreased toxicity to nivolumab; Bifidobacterium and Enterobacter spp., and an unclassified genus of Erysipelotrochaceae were associated with reduced toxicity to dual therapy.

“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).”

May combine two claims.

Akkermansia sp. (R=0.44, P=0.05) and Bifidobacterium sp. (R=0.47, P=0.04) positively correlated with TCR clonality.

“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”

May combine two claims.

In the intention-to-treat population, MPR occurred in 22% (5/23) of the nivolumab arm and 38% (8/21) of the dual arm, with P=0.235.

“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).”

May combine two claims.

Median follow-up after randomization was 22.2 months; median overall survival and lung cancer-related recurrence-free survival were not reached.

“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.”

May combine two claims.

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).

“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).”

May combine two claims.

Radiographic tumor response (CR/PR) was positively associated with MPR in resected patients; all 7 CR/PR patients achieved MPR versus 6/30 (20%) with SD/PD, with P=0.0002.

“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).”

May combine two claims.

Weighted-UniFrac analysis showed similar variability across microbiome communities in pre- and post-therapy samples, with no difference between groups (R=-0.032, P=0.99) or by MPR or TRAE status.

“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).”

May combine two claims.

Nine serious adverse events, five of them treatment related, were noted.

“Nine serious adverse events (five treatment related) were noted (Supplementary Table 5).”

May combine two claims.

Blood T-cell richness increased in most combination therapy samples, whereas blood clonality decreased post-therapy compared with pretherapy.

“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).”

May combine two claims.

Among 37 resected patients, pCR rate was 10% (2/21) for nivolumab and 38% (6/16) for dual therapy, with P=0.055.

“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).”

May combine two claims.

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) negatively correlated with TCR clonality.

“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”

May combine two claims.

Worse lung cancer-related recurrence-free survival was observed in patients with stage IIIA disease compared with stage I/II (P=0.040) and in never smokers compared with current/former smokers (P=0.003).

“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).”

May combine two claims.

After dual therapy compared with nivolumab, resected tumors had higher frequencies of CD45+CD3+ TILs (P=0.021), CD3+CD4+CD103+ non-Treg TRM cells (P=0.041), CD3+CD8+CD103+ effector TRM cells (P=0.057), and CD3+CD4+CD27−CD28+ effector memory T cells (P=0.034).

“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)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Microbiome diversity by inverse Simpson index appeared similar based on MPR status in both arms (P=0.301 and P=0.336).

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

One dual therapy patient had progressive disease 2.6 months after randomization without surgery and died from disease 17.1 months after randomization.

“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.”

May combine two claims.

Pretherapy tumor PD-L1 expression was higher in patients who achieved radiographic response (CR/PR) versus SD/PD (P=0.017) and MPR versus no MPR (P=0.037).

“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.”

May combine two claims.

Among 13 patients with MPR, one death occurred (8%); among 24 without MPR, 3 patients progressed (13%).

“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).”

May combine two claims.

T-cell richness and clonality increased from pretherapy to surgery in 3/3 dual-treated tumors but only 2/4 nivolumab-treated tumors.

“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).”

May combine two claims.

Grade 3-5 treatment-related adverse events occurred in 13% (3/23) of nivolumab patients and 10% (2/21) of dual therapy patients.

“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).”

May combine two claims.

Although higher tumor PD-L1 expression was found in baseline samples from responding patients, responses were also observed in patients lacking pretreatment tumor PD-L1.

“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.”

May combine two claims.

Enhanced T-cell infiltration was observed in tumors treated with combination therapy; however, immune cell infiltration of tumors was independent of MPR.

“We observed enhanced T-cell infiltration in tumors treated with combination therapy; however, immune cell infiltration of tumors was independent of MPR.”

Classified as probably not a substantial claim.

NIF is defined by radiographic progression in lymph nodes that were histologically negative at baseline and then became enlarged or FDG avid after neoadjuvant immune checkpoint inhibitors.

“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.”

May combine two claims.

In the present study, nivolumab monotherapy produced an MPR of 22% in 23 treated patients and 24% in 21 resected tumors.

“In the present study, nivolumab monotherapy produced an MPR of 22% in 23 treated patients and 24% in 21 resected tumors.”

May combine two claims.

In a small subset, treated tumors showed higher TCR richness and clonality than tumor-adjacent uninvolved lung samples, and this was independent of response.

“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.”

May combine two claims.

In the 4 resected patients who received PORT, 2 (50%) had progression; in the 33 who did not receive PORT, 2 (6%) had progression or death.

“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.”

May combine two claims.

In the 13 resected patients with MPR, 1 (8%) died 2.2 months after surgery; in the 24 resected patients without MPR, 3 (13%) had progression at 15.0, 16.4, and 17.9 months after surgery.

“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.”

May combine two claims.

In the adenocarcinoma subgroup of 26 patients, 4 (15%) had progression; in the 18 patients with SCC/ASC, 3 (17%) had progression or death.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A patient who received a single dose of nivolumab plus ipilimumab had a treatment-related serious adverse event, making RECIST response and the percent change in tumor size from baseline unevaluable.

“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.”

May combine two claims.

In the 36 former or current smokers, 3 (8%) had progression; in the 8 never smokers, 4 (50%) had progression or death.

“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.”

May combine two claims.

In the stage I subgroup of 23 patients, 1 (4%) had progression; in the 12 stage II patients, 2 (17%) had progression or death; in the 9 stage IIIA patients, 4 (44%) had progression.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In one patient treated with nivolumab monotherapy, the solid lesion was less than 1 cm after three doses and did not change from baseline, and the response was considered stable disease.

“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.”

May combine two claims.

In the 17 resected patients who received adjuvant chemotherapy, 2 (12%) had progression; in the 20 who did not, 2 (10%) had progression or death.

“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.”

May combine two claims.

41 of 44 patients (93%) completed planned neoadjuvant therapy; 22/23 (96%) in the nivolumab arm and 19/21 (90%) in the dual arm.

“Overall, 41 (93%) patients completed the planned neoadjuvant therapy regimen (nivolumab arm 22 (96%), dual therapy 19 (90%)).”

Probably not a substantial claim: may not pass S3 (load-bearing).

First-line nivolumab plus ipilimumab produced longer overall survival than chemotherapy in advanced NSCLC.

“First-line nivolumab + ipilimumab treatment also produced longer OS than chemotherapy in patients with advanced NSCLC10.”

• cites [10] Hellmann, M. D. et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The trial randomized 44 eligible patients: 23 to nivolumab and 21 to nivolumab plus ipilimumab.

“44 eligible patients were treated on the study, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab + ipilimumab”

May combine two claims.

Perioperative chemotherapy yields only about a 5% improvement in 5-year overall survival and causes toxicity.

“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,”

• cites [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). sourceNot checked yet

  Not checked in the free run.

• cites [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). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The 95% confidence interval of the MPR rate to dual therapy was relatively wide (18-62%), indicating that further studies with a larger sample size could more precisely determine the magnitude of increment compared with chemotherapy alone.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In melanoma, a more clonal T-cell repertoire at baseline correlated with response to neoadjuvant immune checkpoint inhibitor therapy, and pre-existing high-frequency clones expanded further with treatment.

“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.”

• cites [17] Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In prior studies of treatment-naïve and resected NSCLC, higher TCR clonality was found in uninvolved resected lung.

“In contrast, in studies performed in patients with treatment-naïve and resected NSCLC, higher TCR clonality was observed in the uninvolved resected lung22.”

• cites [22] Reuben, A. et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nat. Commun. 11, 603 (2020). sourceNot checked yet

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May combine two claims.

In this 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 maximal immune cell response.

“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.”

May combine two claims.

The toxicity profile was overall manageable with no new safety concerns.

“The toxicity profile was overall manageable with no new safety concerns.”

Classified as probably not a substantial claim.

Previous studies demonstrated that enhanced CD8+CD103+ TRM TILs correlate with improved survival in early stage NSCLC and other cancers.

“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.”

• cites [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). sourceNot checked yet

  Not checked in the free run.

• cites [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). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Studies in melanoma using higher dosages of ipilimumab reported enhanced immune infiltration in responding tumors.

“Studies in melanoma using higher dosages of ipilimumab reported enhanced immune infiltration in responding tumors17.”

• cites [17] Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In melanoma, greater diversity and relative abundance of fecal Ruminococcaceae have been linked to response to immune checkpoint inhibitors.

“Recent studies have shown that higher diversity and relative abundance of fecal Ruminococcaceae are associated with response to ICIs in patients with melanoma26.”

• cites [26] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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 (38% versus 10%).

“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%).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Wei and colleagues showed 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.

“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.”

• cites [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). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Work in other cancers suggests that peripheral T-cell expansion into adjacent uninvolved tissues and tumors is a key determinant of clinical benefit from immunotherapy.

“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.”

• cites [23] Wu, T. D. et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 579, 274–278 (2020). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The movement of T-cell clones from the periphery to resected tumors may reflect recruitment of dominant clones after neoadjuvant therapy.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Histopathologic response to neoadjuvant chemotherapy predicts improved survival more strongly than CT response.

“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.”

• cites [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). sourceNot checked yet

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• cites [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). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The experiments and scorings that produced the presented results were performed only once.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A Bayesian method was used to formally monitor perioperative toxicity within each treatment arm.

“We applied a Bayesian method to formally monitor the toxicity in the perioperative phase within each treatment arm32.”

• cites [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). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Subgating was done only if the parental gate contained more than 100 events.

“Subgating was only performed when more than 100 events were present in parental gate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

No blinding was used in this study.

“No blinding was done as part of this study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The University of Texas MD Anderson Cancer Center Institutional Review Board approved the study.

“The study was approved by the University of Texas MD Anderson Cancer Center’s Institutional Review Board.”

May combine two claims.

The trial lacked statistical power to formally compare the two arms on clinical activity and immune responses; its purpose was to compare tumor responses in both arms against historical chemotherapy controls.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The flow cytometry experiments and gating related to the presented results were performed once.

“Experiments and gating related to the presented results were conducted once.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

To improve interobserver consistency, the two pathologists underwent initial training with co-examination of 5-10 slide samples, then independent examination of 5-10 slide samples, followed by review and consensus agreement on tumor response.

“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.”

• cites [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). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The findings provide evidence that adding neoadjuvant ipilimumab to nivolumab increases MPR and pCR rates and enhances tumor immune infiltrates and immunologic memory.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The Data and Safety Monitoring Board oversaw the study until all participants in arms A and B completed treatment.

“The Data and Safety Monitoring Board provided oversight until all participants randomized to arms A (nivolumab) and B (nivolumab + ipilimumab) completed treatment on study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Randomization was carried out by the clinical trial coordinator using the Department of Biostatistics database system and the Pocock Simon minimization method with stage as a stratification factor.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In advanced NSCLC, front-line nivolumab plus ipilimumab combined with chemotherapy improved survival compared with chemotherapy alone.

“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).”

• cites [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). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The experiments and scorings related to the presented micrographs were performed once.

“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.”

Classified as probably not a substantial claim. May combine two claims.

Pathologic responses were reviewed in a blinded manner by two pathologists experienced in evaluating tumor response after neoadjuvant therapy, and their average scores were used for final analysis.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All study participants or their legal representatives provided written informed consent.

“Written informed consent was provided by all study participants or their legal representatives.”

Classified as probably not a substantial claim.

The prespecified threshold for considering a treatment arm promising for further testing was at least 6 MPRs among 21 evaluable patients.

“The prespecified boundary for a treatment arm to be considered promising for further testing was ≥6 MPRs in 21 evaluable patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Comparisons between the two treatment arms in subsequent analyses were considered exploratory.

“Subsequent analyses comparing the two treatments arms are considered to be exploratory in nature.”

May combine two claims.

When the MPR rate was 15%, the probability of early termination was 60%, the average sample size was 17.4, and the one-sided type I error rate was 10%.

“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.”

May combine two claims.

The number of pre- and post-therapy samples and the number of resected tumor tissues with MPR available for correlative analyses were limited.

“The number of pre- and post-therapy samples and the number of tissues derived from resected tumors with MPR for correlatives was limited.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The reported comparisons are exploratory and hypothesis generating, including the gut microbiome qualitative and correlative analyses.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Prior studies found Akkermansia muciniphila associated with favorable clinical outcomes in melanoma, NSCLC, and renal cell carcinoma patients receiving immune checkpoint inhibitors.

“Similarly, Akkermansia muciniphila was associated with favorable clinical outcomes in patients with melanoma, NSCLC and renal cell carcinoma receiving ICIs in previous studies26,27.”

• cites [26] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [27] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). sourceNot checked yet

  Not checked in the free run.