Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

In the paper

“Until now, the FDA has approved the ipilimumab plus nivolumab for melanoma, RCC, MSI-H/dMMR colorectal cancer, HCC, PD-L1 positive NSCLC, and malignant pleural mesothelioma (Table 5) [132–138].”

What the sources say

• Partly supported

  The Methods and Discussion describe a trial of nivolumab plus ipilimumab in patients with advanced melanoma and report encouraging survival outcomes. That supports the melanoma portion of the multi-citation sentence, but our copy does not state that the FDA approved the combination for melanoma. It also does not address the other listed cancers, which may be covered by the other citations. (LLM, conf=0.84)

  cites [132] Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68. sourceExperimental — accuracy not yet measured
• Partly supported

  The introduction (p. 1536) identifies nivolumab plus ipilimumab as a treatment for advanced melanoma, and the Patients and Treatment section reports a trial arm receiving the combination. Our copy does not establish FDA approval for melanoma or address the other listed indications. (LLM, conf=0.84)

  cites [133] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (p. 1) says the nivolumab–ipilimumab combination is approved for metastatic melanoma. It says nivolumab alone is approved in the United States for dMMR/MSI-H metastatic colorectal cancer, while the Discussion (p. 6) calls the combination a promising new option for those patients. The paper does not establish the claimed combination approvals for RCC, HCC, PD-L1-positive NSCLC, or malignant pleural mesothelioma. (LLM, conf=0.90)

  cites [134] Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with Nivolumab plus Ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal Cancer. J Clin Oncol. 2018;36:773–9. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page not provided) identifies nivolumab plus ipilimumab as a standard-of-care option for first-line treatment of intermediate/poor-risk advanced RCC, supporting the RCC portion of the multi-citation sentence. It does not state that the FDA approved the combination, and it does not address the other listed cancers (searched for FDA approval and approved RCC treatment). (LLM, conf=0.84)

  cites [135] Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20:1370–85. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Discussion report a trial of nivolumab plus ipilimumab in advanced NSCLC with PD-L1 expression of at least 1%, including a survival benefit over chemotherapy. This supports the NSCLC indication associated with this citation, but the paper does not state that the FDA approved the combination for it. (LLM, conf=0.84)

  cites [136] Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung Cancer. N Engl J Med. 2019;381:2020–31. sourceExperimental — accuracy not yet measured
• Supported

  In the multi-citation sentence, CheckMate 743 supports the malignant pleural mesothelioma indication. The Discussion states that the US FDA approved nivolumab plus ipilimumab for first-line treatment of unresectable malignant pleural mesothelioma; this source need not establish the other indications in the list. (LLM, conf=0.93)

  cites [137] Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397:375–86. source
• Supported

  This is one of several citations attached to a list of indications; this paper supports the HCC item. The Introduction states that nivolumab plus ipilimumab was approved in the United States as second-line therapy for HCC, and the Conclusions specify that it received accelerated approval for that use. It does not need to substantiate the other indications in the list. (LLM, conf=0.94)

  cites [138] Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and safety of Nivolumab plus Ipilimumab in patients with advanced hepatocellular carcinoma previously treated with Sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6:e204564. source

In the paper

“RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1 [213, 214].”

What the sources say

• Partly supported

  The Results section (‘Combination MEK inhibition and PD-L1 blockade’; page unavailable) reports a synergistic reduction in KRAS/p53-mutant lung tumor growth and metastasis with MEK inhibition plus anti-PD-L1. It does not establish that RAS-targeted therapy abrogated PI3K-AKT–involved immune evasion, and the benefit was temporary: the tumors ultimately developed resistance. (LLM, conf=0.88)

  cites [213] Peng DH, Rodriguez BL, Diao L, Gaudreau PO, Padhye A, Konen JM, et al. Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers. Nat Commun. 2021;12:2606. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract Results and the Results section on combined MEK and PD-1/PD-L1 inhibition report improved anti-tumor responses with the combination in mouse breast-cancer models. But the intervention was MEK inhibition, not RAS-targeted therapy, and the cited passages do not establish a role for PI3K-AKT in the immune evasion addressed. The Results also note that the interaction effect was not significant in one model, so an unqualified claim of synergy overstates the finding. Page numbers were not provided in our copy. (LLM, conf=0.88)

  cites [214] Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast Cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res. 2016;22:1499–509. sourceExperimental — accuracy not yet measured

In the paper

“As a result, PD-1 signaling suppresses T cell functions, including activation, proliferation, and cytokine production [6].”

What the sources say

• Not checked yetcites [6] Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550. source

In the paper

“Programmed cell death 1 (PD-1) signaling is commonly hijacked by cancer cells to escape immune surveillance [1].”

What the sources say

• Not checked yetcites [1] Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30. source

In the paper

“although 5-fluorouracil, doxorubicin, gemcitabine, and docetaxel reduced circulating myeloid-derived suppressor cells (MDSCs) in mouse models [42–45]”

What the sources say

• Not checked yetcites [42] Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70:3052–61. source
• Not checked yetcites [43] Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74:104–18. source
• Not checked yetcites [44] Zhang Y, Bush X, Yan B, Chen JA. Gemcitabine nanoparticles promote antitumor immunity against melanoma. Biomaterials. 2019;189:48–59. source
• Not checked yetcites [45] Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010;16:4583–94. source

In the paper

“Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, stimulator of interferon genes (STING) agonist, fecal microbiota transplantation (FMT), epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity [22–31].”

What the sources say

• Not checked yetcites [22] Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with Apatinib for advanced hepatocellular carcinoma, gastric, or Esophagogastric junction Cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25:515–23. source
• Not checked yetcites [23] Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line Atezolizumab plus chemotherapy in extensive-stage small-cell lung Cancer. N Engl J Med. 2018;379:2220–9. source
• Not checked yetcites [24] Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and clinical activity of Pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–8. source
• Not checked yetcites [25] Lee SJ, Yang H, Kim WR, Lee YS, Lee WS, Kong SJ, et al. STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer. J Immunother Cancer. 2021;9:e002195. source
• Not checked yetcites [26] Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595–602. source
• Not checked yetcites [27] Ruan H, Hu Q, Wen D, Chen Q, Chen G, Lu Y, et al. A dual-bioresponsive drug-delivery depot for combination of epigenetic modulation and immune checkpoint blockade. Adv Mater. 2019;31:e1806957. source
• Not checked yetcites [28] Ott PA, Hu-Lieskovan S, Chmielowski B, Govindan R, Naing A, Bhardwaj N, et al. A phase Ib trial of personalized Neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung Cancer, or bladder Cancer. Cell. 2020;183:347–62.e24. source
• Not checked yetcites [29] Yuan X, Yi M, Zhang W, Xu L, Chu Q, Luo S, et al. The biology of combination immunotherapy in recurrent metastatic head and neck cancer. Int J Biochem Cell Biol. 2021;136:106002. source
• Not checked yetcites [30] Li A, Yi M, Qin S, Song Y, Chu Q, Wu K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy. J Hematol Oncol. 2019;12:35. source
• Not checked yetcites [31] Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, et al. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol. 2021;14:156. source

In the paper

“Moreover, paclitaxel promoted tumor-associated macrophage (TAM) to repolarize from M2-like to M1-like phenotype [41].”

What the sources say

• Not checked yetcites [41] Wanderley CW, Colón DF, Luiz JPM, Oliveira FF, Viacava PR, Leite CA, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 2018;78:5891–900. source

In the paper

“Collectively, the antigen capture and presentation of DC are enhanced, ultimately motivating adaptive antitumor immune response (Fig. 1a).”

In the paper

“Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity.”

In the paper

“Although α-PD-1/PD-L1 therapies exhibit potent antitumor effects in some patients, most patients could not benefit from α-PD-1/PD-L1 treatments, owing to primary or acquired treatment resistance [13].”

What the sources say

• Not checked yetcites [13] Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492–504. source

In the paper

“On the other hand, some positive factors such as immunogenic cancer cell death, immunosupportive cytokines, and professional antigen presentation cells (pAPCs) contribute to immune clearance [21].”

What the sources say

• Not checked yetcites [21] Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13:143–58. source

In the paper

“Apart from PD-1 signaling, other immune checkpoints, abnormal angiogenesis, immunosuppressive immune cells or cytokines, cancer-associated adipocytes, and hyperactive cancer-associated fibroblasts also modulate cancer-immune set point and promote immune tolerance [15–20].”

What the sources say

• Not checked yetcites [15] Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18:155. source
• Not checked yetcites [16] Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18:60. source
• Not checked yetcites [17] Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019;12:9527–38. source
• Not checked yetcites [18] Liu T, Han C, Wang S, Fang P, Ma Z, Xu L, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019;12:86. source
• Not checked yetcites [19] Yi M, Xu L, Jiao Y, Luo S, Li A, Wu K. The role of cancer-derived microRNAs in cancer immune escape. J Hematol Oncol. 2020;13:25. source
• Not checked yetcites [20] Wu Q, Li B, Li J, Sun S, Yuan J, Sun S. Cancer-associated adipocytes as immunomodulators in cancer. Biomark Res. 2021;9:2. source

In the paper

“At present, antibodies blocking PD-1 or its ligand PD-L1 have been approved to treat various solid and hematologic malignancies (Table 1) [7–12].”

What the sources say

• Not checked yetcites [7] Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375:1823–33. source
• Not checked yetcites [8] Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. source
• Not checked yetcites [9] El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502. source
• Not checked yetcites [10] Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast Cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460–7. source
• Not checked yetcites [11] Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32. source
• Not checked yetcites [12] Tang B, Yan X, Sheng X, Si L, Cui C, Kong Y, et al. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol. 2019;12:7. source

In the paper

“Immunogenic cell death is featured with some upregulated damage-associated molecular patterns (DAMPs) such as the secretion of IFN-I, the exposure of endoplasmic reticulum proteins especially calreticulin (CRT, an eat-me signal) on cell membrane, the leak of ATP (a find-me signal), and the release of high-mobility group box 1 (HMGB1) [35].”

What the sources say

• Not checked yetcites [35] Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–41. source

In the paper

“It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher”

In the paper

“Low-dose cyclophosphamide depleted circulating and tumor-infiltrating regulatory T cells (Tregs) [38–40].”

What the sources say

• Not checked yetcites [38] Barbon CM, Yang M, Wands GD, Ramesh R, Slusher BS, Hedley ML, et al. Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization. Cell Immunol. 2010;262:150–61. source
• Not checked yetcites [39] Tongu M, Harashima N, Monma H, Inao T, Yamada T, Kawauchi H, et al. Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother. 2013;62:383–91. source
• Not checked yetcites [40] Noordam L, Kaijen MEH, Bezemer K, Cornelissen R, Maat L, Hoogsteden HC, et al. Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy. Oncoimmunology. 2018;7:e1474318. source

In the paper

“Besides suppressor cells, some certain chemotherapies such as cyclophosphamide, gemcitabine, and vinblastine recruited and activated DC in the immunogenic cell death manner [47–49].”

What the sources say

• Not checked yetcites [47] Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71:768–78. source
• Not checked yetcites [48] Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, et al. Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget. 2015;6:2250–62. source
• Not checked yetcites [49] Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A. Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res. 2009;69:6987–94. source

In the paper

“some chemotherapeutic agents increased circulating MDSCs in cancer patients [46]”

What the sources say

• Not checked yetcites [46] Wesolowski R, Duggan MC, Stiff A, Markowitz J, Trikha P, Levine KM, et al. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol Immunother. 2017;66:1437–47. source

In the paper

“Later in 2021, the NMPA approved camrelizumab plus gemcitabine and cisplatin (for advanced nasopharyngeal carcinoma) and tislelizumab plus chemotherapy (for NSCLC) [62–64].”

What the sources say

• Not checked yetcites [62] Yang Y, Qu S, Li J, Hu C, Xu M, Li W, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22:1162–74. source
• Not checked yetcites [63] Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non-small-cell lung Cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7:709–17. source
• Not checked yetcites [64] Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol. 2021;16:1512–22. source

In the paper

“In the clinical trial KEYNOTE-021 (phase 2), non-squamous non-small cell lung cancer (NSCLC) patients receiving pembrolizumab combined with standard chemotherapy (carboplatin and pemetrexed) had a higher response rate and longer progression-free survival (PFS) than did patients receiving standard chemotherapy [52].”

What the sources say

• Not checked yetcites [52] Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497–508. source

In the paper

“Subsequently, the FDA approved atezolizumab plus chemotherapy for TNBC (atezolizumab plus nab-paclitaxel, based on IMpassion130), SCLC (atezolizumab plus carboplatin and etoposide, based on IMpower133), and non-squamous NSCLC (atezolizumab plus nab-paclitaxel and carboplatin, based on IMpower130) [66–68].”

What the sources say

• Not checked yetcites [66] Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59. source
• Not checked yetcites [67] Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020;31:310–7. source
• Not checked yetcites [68] West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924–37. source

In the paper

“Based on the results of KEYNOTE-021, pembrolizumab plus chemotherapy has been approved by the FDA as the first-line treatment for advanced non-squamous NSCLC, regardless of PD-L1 level [52].”

What the sources say

• Not checked yetcites [52] Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497–508. source

In the paper

“Subsequently, the FDA approved atezolizumab plus chemotherapy for TNBC (atezolizumab plus nab-paclitaxel, based on IMpassion130), SCLC (atezolizumab plus carboplatin and etoposide, based on IMpower133), and non-squamous NSCLC (atezolizumab plus nab-paclitaxel and carboplatin, based on IMpower130) [66–68].”

What the sources say

• Not checked yetcites [66] Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59. source
• Not checked yetcites [67] Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020;31:310–7. source
• Not checked yetcites [68] West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924–37. source

In the paper

“Also, chemotherapeutic drugs such as vinblastine, 5-fluorouracil, and oxaliplatin, could directly enhance the functions of DC and promote IL-12 secretion [49, 50].”

What the sources say

• Not checked yetcites [49] Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A. Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res. 2009;69:6987–94. source
• Not checked yetcites [50] Hong X, Dong T, Yi T, Hu J, Zhang Z, Lin S, et al. Impact of 5-Fu/oxaliplatin on mouse dendritic cells and synergetic effect with a colon cancer vaccine. Chin J Cancer Res. 2018;30:197–208. source

In the paper

“The FDA rarely approves chemoimmunotherapeutic strategies with other α-PD-1 drugs (except for nivolumab combined with chemotherapy for gastric cancer and GEJC) [58].”

What the sources say

• Not checked yetcites [58] Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyrwicz L, et al. LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020. https://doi.org/10.1016/j.annonc.2020.08.2296. source

In the paper

“In 2020, the NMPA also approved camrelizumab plus carboplatin and pemetrexed as the first-line treatment for non-squamous NSCLC, based on the results of CameL [61].”

What the sources say

• Not checked yetcites [61] Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021;9:305–14. source

In the paper

“Nowadays, chemotherapy combined with α-PD-1/PD-L1 has become a standard-of-care option for some cancer patients, and there are hundreds of ongoing clinical trials exploring the efficacy and safety of chemotherapy plus α-PD-1/PD-L1 (Table 2).”

In the paper

“Based on the immune-modulatory effect of chemotherapeutic agents, chemotherapy might be an appropriate partner with α-PD-1/PD-L1 to achieve both rapid and long-term cancer control.”

In the paper

“Moreover, based on the results of CASPIAN, durvalumab combined with platinum plus etoposide therapy was approved for SCLC in the US [69].”

What the sources say

• Not checked yetcites [69] Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929–39. source

In the paper

“In addition, the NMPA approved sintilimab plus gemcitabine and platinum as the first-line treatment for advanced squamous NSCLC, based on the results of ORIENT-12 [60].”

What the sources say

• Not checked yetcites [60] Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol. 2021;16:1501–11. source

In the paper

“The results of the phase 1 study NCT02608385 demonstrated that α-PD-1/PD-L1 combined with SBRT was well-tolerable (Table 3) [24].”

What the sources say

• Not checked yetcites [24] Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and clinical activity of Pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–8. source

In the paper

“Later, in two phase 3 clinical studies (KEYNOTE-189 and KEYNOTE-407), pembrolizumab combined with standard chemotherapy led to a better overall survival (OS) and PFS in NSCLC patients, relative to chemotherapy monotherapy [53, 54].”

What the sources say

• Not checked yetcites [53] Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung Cancer. N Engl J Med. 2018;378:2078–92. source
• Not checked yetcites [54] Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung Cancer. N Engl J Med. 2018;379:2040–51. source

In the paper

“In the phase 2 study NCT02904954, SBRT combined with durvalumab acquired a superior antitumor effect to durvalumab in early-stage NSCLC [83].”

What the sources say

• Not checked yetcites [83] Altorki NK, McGraw TE, Borczuk AC, Saxena A, Port JL, Stiles BM, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-Centre, randomised phase 2 trial. Lancet Oncol. 2021;22:824–35. source

In the paper

“Moreover, the results of some phase 1/2 studies (NCT02621398, NCT02434081, NCT02586207, NCT02383212, and NCT02402920) showed that α-PD-1/PD-L1 plus chemoradiotherapy was tolerable in advanced NSCLC, head and neck squamous cell carcinoma (HNSCC), and SCLC patients, with promising clinical outcomes [78–82].”

What the sources say

• Not checked yetcites [78] Jabbour SK, Berman AT, Decker RH, Lin Y, Feigenberg SJ, Gettinger SN, et al. Phase 1 trial of Pembrolizumab administered concurrently with Chemoradiotherapy for locally advanced non-small cell lung Cancer: a nonrandomized controlled trial. JAMA Oncol. 2020;6:848–55. source
• Not checked yetcites [79] Powell SF, Gold KA, Gitau MM, Sumey CJ, Lohr MM, McGraw SC, et al. Safety and efficacy of Pembrolizumab with Chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a phase IB study. J Clin Oncol. 2020;38:2427–37. source
• Not checked yetcites [80] Peters S, Felip E, Dafni U, Belka C, Guckenberger M, Irigoyen A, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial. Lung Cancer. 2019;133:83–7. source
• Not checked yetcites [81] Papadopoulos KP, Johnson ML, Lockhart AC, Moore K, Falchook GS, Formenti SC, et al. First-in-human study of Cemiplimab alone or in combination with radiotherapy and/or low-dose cyclophosphamide in patients with advanced malignancies. Clin Cancer Res. 2020;26:1025–33. source
• Not checked yetcites [82] Welsh JW, Heymach JV, Guo C, Menon H, Klein K, Cushman TR, et al. Phase 1/2 trial of Pembrolizumab and concurrent Chemoradiation therapy for limited-stage SCLC. J Thorac Oncol. 2020;15:1919–27. source

In the paper

“The major pathological response rate was significantly higher in the SBRT combined with durvalumab arm than that in the durvalumab arm [83].”

What the sources say

• Not checked yetcites [83] Altorki NK, McGraw TE, Borczuk AC, Saxena A, Port JL, Stiles BM, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-Centre, randomised phase 2 trial. Lancet Oncol. 2021;22:824–35. source

In the paper

“Based on the results of IMpower150, the FDA approved atezolizumab plus bevacizumab, paclitaxel, and carboplatin as the first-line treatment for advanced non-squamous NSCLC [65].”

What the sources say

• Not checked yetcites [65] Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288–301. source

In the paper

“Subsequently, the FDA approved atezolizumab plus chemotherapy for TNBC (atezolizumab plus nab-paclitaxel, based on IMpassion130), SCLC (atezolizumab plus carboplatin and etoposide, based on IMpower133), and non-squamous NSCLC (atezolizumab plus nab-paclitaxel and carboplatin, based on IMpower130) [66–68].”

What the sources say

• Not checked yetcites [66] Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59. source
• Not checked yetcites [67] Mansfield AS, Każarnowicz A, Karaseva N, Sánchez A, De Boer R, Andric Z, et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol. 2020;31:310–7. source
• Not checked yetcites [68] West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924–37. source

In the paper

“Later in 2021, the NMPA approved camrelizumab plus gemcitabine and cisplatin (for advanced nasopharyngeal carcinoma) and tislelizumab plus chemotherapy (for NSCLC) [62–64].”

What the sources say

• Not checked yetcites [62] Yang Y, Qu S, Li J, Hu C, Xu M, Li W, et al. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22:1162–74. source
• Not checked yetcites [63] Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non-small-cell lung Cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7:709–17. source
• Not checked yetcites [64] Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol. 2021;16:1512–22. source

In the paper

“In China, the NMPA approved sintilimab plus pemetrexed and platinum as the first-line treatment for advanced non-squamous NSCLC, based on the results of ORIENT-11 [59].”

What the sources say

• Not checked yetcites [59] Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, et al. Efficacy and safety of Sintilimab plus Pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020;15:1636–46. source

In the paper

“Additionally, pemetrexed enhanced the activation of tumor-infiltrating lymphocytes (TILs) by improving mitochondrial biogenesis, independent of immunogenic cell death [51].”

What the sources say

• Not checked yetcites [51] Schaer DA, Geeganage S, Amaladas N, Lu ZH, Rasmussen ER, Sonyi A, et al. The Folate pathway inhibitor Pemetrexed Pleiotropically enhances effects of Cancer immunotherapy. Clin Cancer Res. 2019;25:7175–88. source

In the paper

“The disorganized angiogenesis promotes the formation of the immunosuppressive TME [16].”

What the sources say

• Not checked yetcites [16] Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18:60. source

In the paper

“Furthermore, in the phase 3 study NCT02952586 exploring the efficacy of avelumab plus standard-of-care chemoradiotherapy in HNSCC, it did not meet the primary endpoint (PFS) [86].”

What the sources say

• Not checked yetcites [86] Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22:450–62. source

In the paper

“Additionally, the results of the phase 3 study NCT02125461 indicated that sequential durvalumab treatment markedly improved the PFS and OS of NSCLC patients undergoing chemoradiotherapy [84].”

What the sources say

• Not checked yetcites [84] Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with Durvalumab after Chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–50. source

In the paper

“At a median follow-up time of 30.6 months, the median OS and PFS were longer in the pembrolizumab combined with axitinib arm compared to those in the sunitinib arm [109].”

What the sources say

• Not checked yetcites [109] Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21:1563–73. source

In the paper

“However, multiple studies have been confirmed that antibody-dependent cell-mediated cytotoxicity of Treg also substantially contributes to the antitumor activity of ipilimumab [128–130].”

What the sources say

• Not checked yetcites [128] Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A. 2015;112:6140–5. source
• Not checked yetcites [129] Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695–710. source
• Not checked yetcites [130] Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell. 2018;33:649–63.e4. source

In the paper

“In the multiple preclinical studies, angiogenesis inhibitor enhanced the efficacy of α-PD-1/PD-L1 in murine tumor models [106–108].”

What the sources say

• Not checked yetcites [106] Wu FTH, Xu P, Chow A, Man S, Krüger J, Khan KA, et al. Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease. Br J Cancer. 2019;120:196–206. source
• Not checked yetcites [107] Schmittnaegel M, Rigamonti N, Kadioglu E, Cassará A, Wyser Rmili C, Kiialainen A, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017;9:eaak9670. source
• Not checked yetcites [108] Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017;9:eaak9679. source

In the paper

“However, in the phase 2 study NCT02684253, SBRT combined with nivolumab was not superior to nivolumab in response rate, PFS, and OS in advanced HNSCC [85].”

What the sources say

• Not checked yetcites [85] McBride S, Sherman E, Tsai CJ, Baxi S, Aghalar J, Eng J, et al. Randomized phase II trial of Nivolumab with stereotactic body radiotherapy versus Nivolumab alone in metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2021;39:30–7. source

In the paper

“In 2019, pembrolizumab combined with axitinib was approved by the FDA as the first-line treatment for advanced RCC, based on the results of KEYNOTE-426 (Table 4) [109].”

What the sources say

• Not checked yetcites [109] Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21:1563–73. source

In the paper

“Moreover, pembrolizumab plus lenvatinib was also approved for advanced endometrial carcinoma [110].”

What the sources say

• Not checked yetcites [110] Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20:711–8. source

In the paper

“Although both CTLA-4 and PD-1 are immune checkpoints, they inhibit T cell activation in nonredundant manners.”

In the paper

“On the other hand, CTLA-4 engagement with CD80/CD86 counteracts TCR-induced downstream signaling and suppresses PI3K-Akt pathway (vital signaling of T cell activation), via SHP-2 and protein phosphatase 2A (PP2A) [123, 124].”

What the sources say

• Not checked yetcites [123] Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53. source
• Not checked yetcites [124] Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282:2263–6. source

In the paper

“Besides pembrolizumab plus axitinib, nivolumab plus cabozantinib (based on CheckMate-9ER) [112] and avelumab plus axitinib (based on JAVELIN Renal 101) [113] were also approved by the FDA as the initial-line treatment for RCC.”

What the sources say

• Not checked yetcites [112] Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus Cabozantinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829–41. source

In the paper

“Besides pembrolizumab plus axitinib, nivolumab plus cabozantinib (based on CheckMate-9ER) [112] and avelumab plus axitinib (based on JAVELIN Renal 101) [113] were also approved by the FDA as the initial-line treatment for RCC.”

What the sources say

• Not checked yetcites [113] Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN renal 101 trial. Nat Med. 2020;26:1733–41. source

In the paper

“Combination therapies such as sintilimab plus anlotinib, sintilimab plus IBI305 (bevacizumab biosimilar), camrelizumab plus apatinib, and toripalimab plus axitinib demonstrated potent antitumor effects in multiple types of cancers [22, 114–120].”

What the sources say

• Not checked yetcites [22] Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, et al. Anti-PD-1 antibody SHR-1210 combined with Apatinib for advanced hepatocellular carcinoma, gastric, or Esophagogastric junction Cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25:515–23. source
• Not checked yetcites [114] Xie L, Xu J, Sun X, Guo W, Gu J, Liu K, et al. Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial. J Immunother Cancer. 2020;8:e000798. source
• Not checked yetcites [115] Liu J, Liu Q, Li Y, Li Q, Su F, Yao H, et al. Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial. J Immunother Cancer. 2020;8:e000696. source
• Not checked yetcites [116] Lan C, Shen J, Wang Y, Li J, Liu Z, He M, et al. Camrelizumab plus Apatinib in patients with advanced cervical Cancer (CLAP): a multicenter, open-label, single-arm, Phase II Trial. J Clin Oncol. 2020;38:4095–106. source
• Not checked yetcites [117] Fan Y, Zhao J, Wang Q, Huang D, Li X, Chen J, et al. Camrelizumab plus Apatinib in extensive-stage SCLC (PASSION): a multicenter, two-stage, phase 2 trial. J Thorac Oncol. 2021;16:299–309. source
• Not checked yetcites [118] Chu T, Zhong R, Zhong H, Zhang B, Zhang W, Shi C, et al. Phase 1b study of Sintilimab plus Anlotinib as first-line therapy in patients with advanced NSCLC. J Thorac Oncol. 2021;16:643–52. source
• Not checked yetcites [119] Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22:977–90. source
• Not checked yetcites [120] Sheng X, Yan X, Chi Z, Si L, Cui C, Tang B, et al. Axitinib in combination with Toripalimab, a humanized immunoglobulin G(4) monoclonal antibody against programmed cell Death-1, in patients with metastatic mucosal melanoma: an open-label phase IB trial. J Clin Oncol. 2019;37:2987–99. source

In the paper

“On the one hand, CTLA-4 could competitively suppress the binding of CD28 to CD80/CD86, halting the secondary signal of T cell activation [122].”

What the sources say

• Not checked yetcites [122] Choi JM, Ahn MH, Chae WJ, Jung YG, Park JC, Song HM, et al. Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Nat Med. 2006;12:574–9. source

In the paper

“Up to now, most angiogenesis inhibitor plus α-PD-1/PD-L1 strategies are undergoing clinical trials, having not been approved by the FDA or NMPA.”

In the paper

“Then, in 2020, the FDA approved atezolizumab combined with bevacizumab for advanced HCC based on the data of IMbrave150 [111].”

What the sources say

• Not checked yetcites [111] Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382:1894–905. source

In the paper

“Additionally, CTLA-4 could capture, remove, and degrade its ligands CD80/CD86 from nearby APCs by trans-endocytosis, further hampering the co-stimulatory signal [125].”

What the sources say

• Not checked yetcites [125] Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332:600–3. source

In the paper

“The results of CheckMate-069, CheckMate-067, and CheckMate-142 showed that ipilimumab plus nivolumab significantly improved the outcomes of patients, relative to ipilimumab or nivolumab monotherapies [132–134].”

What the sources say

• Not checked yetcites [132] Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68. source
• Not checked yetcites [133] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46. source
• Not checked yetcites [134] Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with Nivolumab plus Ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal Cancer. J Clin Oncol. 2018;36:773–9. source

In the paper

“Apart from efficacy, it is concerned that dual PD-1/PD-L1 and CTLA-4 blockade might lead to serious immune-related adverse events (irAEs) such as colitis, hypophysitis, pneumonitis, and thyroiditis [153].”

What the sources say

• Not checked yetcites [153] Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–68. source

In the paper

“A series of preclinical studies showed that co-stimulatory molecule agonists improved α-PD-1/PD-L1 efficacy [170–176].”

What the sources say

• Not checked yetcites [170] McGray AJR, Eppolito C, Miliotto A, Singel KL, Stephenson K, Lugade A, et al. A prime/boost vaccine platform efficiently identifies CD27 agonism and depletion of myeloid-derived suppressor cells as therapies that rationally combine with checkpoint blockade in ovarian cancer. Cancer Immunol Immunother. 2021;70:3451–60. source
• Not checked yetcites [171] Buchan SL, Fallatah M, Thirdborough SM, Taraban VY, Rogel A, Thomas LJ, et al. PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8(+) T-cell-driven antitumor immunity. Clin Cancer Res. 2018;24:2383–94. source
• Not checked yetcites [172] Diggs LP, Ruf B, Ma C, Heinrich B, Cui L, Zhang Q, et al. CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma. J Hepatol. 2021;74:1145–54. source
• Not checked yetcites [173] Qu QX, Zhu XY, Du WW, Wang HB, Shen Y, Zhu YB, et al. 4-1BB Agonism combined with PD-L1 blockade increases the number of tissue-resident CD8+ T cells and facilitates tumor abrogation. Front Immunol. 2020;11:577. source
• Not checked yetcites [174] Ma Y, Li J, Wang H, Chiu Y, Kingsley CV, Fry D, et al. Combination of PD-1 inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic Cancer. Gastroenterology. 2020;159:306–19.e12. source
• Not checked yetcites [175] Wang B, Zhang W, Jankovic V, Golubov J, Poon P, Oswald EM, et al. Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8(+) T cell dysfunction and maintain memory phenotype. Sci Immunol. 2018;3:eaat7061. source
• Not checked yetcites [176] Hanson A, Elpek K, Duong E, Shallberg L, Fan M, Johnson C, et al. ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models. PLoS One. 2020;15:e0239595. source

In the paper

“Therefore, ipilimumab is commonly administrated at a reduced dose [154], which might weaken the efficacy of combination therapy.”

In the paper

“A preclinical study found that prophylactic TNF blockade could dissociate the efficacy and toxicity of α-CTLA-4 plus α-PD-1/PD-L1 therapy [155].”

What the sources say

• Not checked yetcites [155] Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019;569:428–32. source

In the paper

“The results of clinical trials showed that α-TIM-3 plus α-PD-1/PD-L1 was tolerable without unexpected safety signals, but more efforts are needed for patient selection [158–160].”

What the sources say

• Not checked yetcites [158] Harding JJ, Moreno V, Bang YJ, Hong MH, Patnaik A, Trigo J, et al. Blocking TIM-3 in treatment-refractory advanced solid tumors: a phase Ia/b study of LY3321367 with or without an anti-PD-L1 antibody. Clin Cancer Res. 2021;27:2168–78. source
• Not checked yetcites [159] Hollebecque A, Chung HC, de Miguel MJ, Italiano A, Machiels JP, Lin CC, et al. Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors. Clin Cancer Res. 2021. https://doi.org/10.1158/1078-0432.CCR-21-0261. source
• Not checked yetcites [160] Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, et al. Phase I/Ib clinical trial of Sabatolimab, an anti-TIM-3 antibody, alone and in combination with Spartalizumab, an anti-PD-1 antibody, in advanced solid tumors. Clin Cancer Res. 2021;27:3620–9. source

In the paper

“Therefore, ipilimumab is commonly administrated at a reduced dose [154], which might weaken the efficacy of combination therapy.”

What the sources say

• Not checked yetcites [154] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. source

In the paper

“Moreover, the data of CheckMate-214, CheckMate-227, and CheckMate-743 indicated the superior efficacy of ipilimumab plus nivolumab over the standard targeted therapy or chemotherapy [135–137].”

What the sources say

• Not checked yetcites [135] Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20:1370–85. source
• Not checked yetcites [136] Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung Cancer. N Engl J Med. 2019;381:2020–31. source
• Not checked yetcites [137] Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397:375–86. source

In the paper

“Agonists targeting co-stimulatory pathways could enhance T cell activity and revolve antitumor immune response [169].”

What the sources say

• Not checked yetcites [169] Pourakbari R, Hajizadeh F, Parhizkar F, Aghebati-Maleki A, Mansouri S, Aghebati-Maleki L. Co-stimulatory agonists: an insight into the immunotherapy of cancer. EXCLI J. 2021;20:1055–85.

In the paper

“Accumulating evidence has indicated that dual PD-1/PD-L1 and CTLA-4 blockade has superior antitumor activity in some types of cancers [131].”

What the sources say

• Not checked yetcites [131] Wu K, Yi M, Qin S, Chu Q, Zheng X, Wu K. The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis. Exp Hematol Oncol. 2019;8:26. source

In the paper

“The engagement of TIM-3 with its ligand galectin-9 led to Th1 cell death by triggering intracellular calcium flux [156].”

What the sources say

• Not checked yetcites [156] Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52. source

In the paper

“Therefore, α-CTLA-4 might cooperate with α-PD-1/PD-L1 to boost the antitumor immune response.”

In the paper

“Other dual immune checkpoint blockade strategies, including α-PD-1/PD-L1 combined with α-TIM-3, α-LAG-3, α-PVRIG, α-TIGIT, are still in clinical trials, having not been approved by the FDA or NMPA.”

In the paper

“However, the subgroup analysis showed that tremelimumab plus durvalumab markedly improved the OS of NSCLC patients with a high tumor mutation burden [145], indicating the importance of appropriate patient selection for the optimal benefit of tremelimumab plus durvalumab.”

In the paper

“Besides co-inhibitory pathways such as PD-1 and CTLA-4, co-stimulatory pathways including CD27/CD70, CD40/CD40L, 4-1BB/4-1BBL, OX40/OX40L, GITR/GITRL, and ICOS/ICOSL also regulate T cell function (Fig. 2a) [168].”

What the sources say

• Not checked yetcites [168] Marin-Acevedo JA, Kimbrough EO, Manochakian R, Zhao Y, Lou Y. Immunotherapies targeting stimulatory pathways and beyond. J Hematol Oncol. 2021;14:78. source

In the paper

“Besides α-TIM-3, other ICIs such as α-LAG-3, α-PVRIG, α-TIGIT, α- Siglec-10 also synergized with α-PD-1/PD-L1 in enhancing TIL function and suppressing tumor growth [161–164].”

What the sources say

• Not checked yetcites [161] Gestermann N, Saugy D, Martignier C, Tillé L, Fuertes Marraco SA, Zettl M, et al. LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures. Oncoimmunology. 2020;9:1736792. source
• Not checked yetcites [162] Li Y, Zhang Y, Cao G, Zheng X, Sun C, Wei H, et al. Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors. J Hematol Oncol. 2021;14:100. source
• Not checked yetcites [163] Mao L, Xiao Y, Yang QC, Yang SC, Yang LL, Sun ZJ. TIGIT/CD155 blockade enhances anti-PD-L1 therapy in head and neck squamous cell carcinoma by targeting myeloid-derived suppressor cells. Oral Oncol. 2021;121:105472. source
• Not checked yetcites [164] Xiao N, Zhu X, Li K, Chen Y, Liu X, Xu B, et al. Blocking siglec-10(hi) tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma. Exp Hematol Oncol. 2021;10:36. source

In the paper

“In the phase 2/3 study RELATIVITY-047, relatlimab (α-LAG-3) plus nivolumab therapy demonstrated a significant PFS benefit (10.1 vs. 4.6 months, HR: 0.75) in advanced melanoma, relatively to nivolumab monotherapy [165].”

What the sources say

• Not checked yetcites [165] Lipson EJ, Tawbi HA-H, Schadendorf D, Ascierto PA, Matamala L, Gutiérrez EC, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.9503. source

In the paper

“Moreover, in the phase 1 study NCT03667716, COM701 (α-PVRIG) plus nivolumab exhibited encouraging antitumor activity even in some patients with prior ICI treatment [166].”

What the sources say

• Not checked yetcites [166] Vaena DA, Fleming GF, Chmielowski B, Sharma M, Hamilton EP, Sullivan RJ, et al. COM701 with or without nivolumab: results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716). J Clin Oncol. 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.2504. source

In the paper

“However, the subgroup analysis showed that tremelimumab plus durvalumab markedly improved the OS of NSCLC patients with a high tumor mutation burden [145], indicating the importance of appropriate patient selection for the optimal benefit of tremelimumab plus durvalumab.”

What the sources say

• Not checked yetcites [145] Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, et al. Durvalumab with or without Tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung Cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6:661–74. source

In the paper

“Similar to EGFR-mutation, ALK rearrangement is also related to the poor response to α-PD-1/PD-L1 [199].”

What the sources say

• Not checked yetcites [199] Garassino MC, Cho BC, Kim JH, Mazières J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018;19:521–36. source

In the paper

“However, a retrospective study found that patients receiving nivolumab plus erlotinib might have a higher risk of treatment-associated interstitial pneumonitis (Odds ratio: 4.31, P < 0.001), relative to patients undergoing EGFR-TKI monotherapy [191].”

What the sources say

• Not checked yetcites [191] Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in Nivolumab-treated patients with non-small cell lung Cancer. JAMA Oncol. 2018;4:1112–5. source

In the paper

“Generally believed, the efficacy of α-PD-1/PD-L1 is modest in EGFR-mutated patients [184, 185]”

What the sources say

• Not checked yetcites [184] Qiao M, Jiang T, Liu X, Mao S, Zhou F, Li X, et al. Immune checkpoint inhibitors in EGFR-mutated NSCLC: dusk or Dawn? J Thorac Oncol. 2021;16:1267–88. source
• Not checked yetcites [185] Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, et al. A phase II study of Pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor Naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13:1138–45. source

In the paper

“Combination therapy of α-PD-1 and ceritinib had an enhanced antitumor efficacy in NPM1-ALK+ R80 model [202].”

What the sources say

• Not checked yetcites [202] Petrazzuolo A, Perez-Lanzon M, Martins I, Liu P, Kepp O, Minard-Colin V, et al. Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects. Cell Death Dis. 2021;12:713. source

In the paper

“In the phase 1/2 study CheckMate-370, 38% of patients receiving nivolumab plus crizotinib developed severe hepatic toxicities, leading to the termination of the enrollment [203].”

What the sources say

• Not checked yetcites [203] Spigel DR, Reynolds C, Waterhouse D, Garon EB, Chandler J, Babu S, et al. Phase 1/2 study of the safety and tolerability of Nivolumab plus Crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung Cancer (CheckMate 370). J Thorac Oncol. 2018;13:682–8. source

In the paper

“Because of the increased risk of treatment-associated interstitial lung disease, a phase 3 clinical trial CAURAL was stopped early [193].”

What the sources say

• Not checked yetcites [193] Yang JC, Shepherd FA, Kim DW, Lee GW, Lee JS, Chang GC, et al. Osimertinib plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report. J Thorac Oncol. 2019;14:933–9. source

In the paper

“which might be attributed to the lack of concurrent TIL and PD-L1 expression, low tumor mutation burden, or increased Tregs in the TME [186].”

What the sources say

• Not checked yetcites [186] Huang MY, Jiang XM, Wang BL, Sun Y, Lu JJ. Combination therapy with PD-1/PD-L1 blockade in non-small cell lung cancer: strategies and mechanisms. Pharmacol Ther. 2021;219:107694. source

In the paper

“It should be noted that ALK-TKI combined with α-PD-1/PD-L1 might increase treatment-associated hepatotoxicity.”

What the sources say

• Not checked yetcites [203] Spigel DR, Reynolds C, Waterhouse D, Garon EB, Chandler J, Babu S, et al. Phase 1/2 study of the safety and tolerability of Nivolumab plus Crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung Cancer (CheckMate 370). J Thorac Oncol. 2018;13:682–8. source
• Not checked yetcites [204] Patel SP, Pakkala S, Pennell NA, Reckamp KL, Lanzalone S, Polli A, et al. Phase Ib study of Crizotinib plus Pembrolizumab in patients with previously untreated advanced non-small cell lung Cancer with ALK translocation. Oncologist. 2020;25:562–e1012. source

In the paper

“Moreover, pembrolizumab plus crizotinib also showed intolerable hepatotoxicity in NSCLC [204].”

What the sources say

• Not checked yetcites [204] Patel SP, Pakkala S, Pennell NA, Reckamp KL, Lanzalone S, Polli A, et al. Phase Ib study of Crizotinib plus Pembrolizumab in patients with previously untreated advanced non-small cell lung Cancer with ALK translocation. Oncologist. 2020;25:562–e1012. source

In the paper

“Some cancers especially NSCLC are addicted to the hyperactive EGFR pathway [183].”

What the sources say

• Not checked yetcites [183] Recondo G, Facchinetti F, Olaussen KA, Besse B, Friboulet L. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol. 2018;15:694–708. source

In the paper

“Collectively, EGFR-TKI plus α-PD-1/PD-L1 therapy would maximize the efficacy of immunotherapy in patients with EGFR-mutated cancers (Fig. 2b).”

In the paper

“Besides, activated EGFR signaling contributes to the upregulated PD-L1 on cancer cells, and EGFR-TKI might cooperate with α-PD-1/PD-L1 to attenuate immune evasion [188].”

What the sources say

• Not checked yetcites [188] Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021;14:10. source

In the paper

“Additionally, in the phase 1 study TATTON, the incidence rate of interstitial lung disease in the osimertinib (a third-generation EGFR-TKI) plus durvalumab arm was unexpectedly high (22%), leading to the termination of patient enrollment [192].”

What the sources say

• Not checked yetcites [192] Oxnard GR, Yang JC, Yu H, Kim SW, Saka H, Horn L, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020;31:507–16. source

In the paper

“The ORR of combination therapy was as high as 75% in the expansion-stage group”

What the sources say

• Not checked yetcites [190] Rudin C, Cervantes A, Dowlati A, Besse B, Ma B, Costa D, et al. P3.02c-046 safety, clinical activity and biomarker results from a phase Ib study of Erlotinib plus Atezolizumab in advanced NSCLC. J Thorac Oncol. 2017. https://doi.org/10.1016/j.jtho.2016.11.1841. source

In the paper

“This phenomenon appears to be unique to osimertinib [194].”

What the sources say

• Not checked yetcites [194] Schoenfeld AJ, Arbour KC, Rizvi H, Iqbal AN, Gadgeel SM, Girshman J, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839–44. source

In the paper

“it has been confirmed that treatment sequence and timing are closely associated with the incidence of irAE.”

What the sources say

• Not checked yetcites [194] Schoenfeld AJ, Arbour KC, Rizvi H, Iqbal AN, Gadgeel SM, Girshman J, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839–44. source

In the paper

“Besides, activated EGFR signaling contributes to the upregulated PD-L1 on cancer cells, and EGFR-TKI might cooperate with α-PD-1/PD-L1 to attenuate immune evasion [188].”

What the sources say

• Not checked yetcites [188] Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021;14:10. source

In the paper

“Additionally, the timing and sequence of combination therapy also influence treatment toxicity, which should be further validated in clinical studies [186, 207].”

What the sources say

• Not checked yetcites [186] Huang MY, Jiang XM, Wang BL, Sun Y, Lu JJ. Combination therapy with PD-1/PD-L1 blockade in non-small cell lung cancer: strategies and mechanisms. Pharmacol Ther. 2021;219:107694. source
• Not checked yetcites [207] Lin JJ, Chin E, Yeap BY, Ferris LA, Kamesan V, Lennes IT, et al. Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and Crizotinib therapy in patients with non-small cell lung Cancer. J Thorac Oncol. 2019;14:135–40. source

In the paper

“Therefore, agents targeting EGFR could effectively suppress the growth of these EGFR-addictive cancers.”

In the paper

“tumor-infiltrating CD8+ T cell was increased in 8/13 paired biopsies after 7-day erlotinib treatment [190].”

What the sources say

• Not checked yetcites [190] Rudin C, Cervantes A, Dowlati A, Besse B, Ma B, Costa D, et al. P3.02c-046 safety, clinical activity and biomarker results from a phase Ib study of Erlotinib plus Atezolizumab in advanced NSCLC. J Thorac Oncol. 2017. https://doi.org/10.1016/j.jtho.2016.11.1841. source

In the paper

“However, in the phase 2 study NCT02322814, atezolizumab plus cobimetinib and taxane had no improvement in ORR in TNBC, relative to cobimetinib plus taxane [216].”

What the sources say

• Not checked yetcites [216] Brufsky A, Kim SB, Zvirbule Ž, Eniu A, Mebis J, Sohn JH, et al. A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis. Ann Oncol. 2021;32:652–60. source

In the paper

“Dysregulated fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling participates in cancer development by activating MAPK, PI3K, and PLC-γ pathways [232, 233].”

What the sources say

• Not checked yetcites [232] Yue S, Li Y, Chen X, Wang J, Li M, Chen Y, et al. FGFR-TKI resistance in cancer: current status and perspectives. J Hematol Oncol. 2021;14:23. source
• Not checked yetcites [233] Liang Q, Wang J, Zhao L, Hou J, Hu Y, Shi J. Recent advances of dual FGFR inhibitors as a novel therapy for cancer. Eur J Med Chem. 2021;214:113205. source

In the paper

“Besides, olaparib and durvalumab arm also had a higher ORR than that reported for PARPi treatment in germline BRCA-mutated platinum-sensitive relapsed ovarian cancer [229].”

What the sources say

• Not checked yetcites [229] Drew Y, de Jonge M, Hong SH, Park YH, Wolfer A, Brown J, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gynecol Oncol. 2018;149:246–7. source