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Background: To investigate the role of pretreatment lung immune prognostic index (LIPI) as biomarker in PD-L1 ≥50% non-small-cell lung cancer patients receiving pembrolizumab. Patients & methods: We retrospectively identified 117 patients, divided into three prognostic groups according to LIPI score. For each patient, we evaluated 1-year overall survival (OS) and progression-free survival rate. C-statistic and survival receiver operating characteristic curves were used to study discrimination of LIPI. Results: After a median follow-up of 11.7 months, 1-year OS rate was 60.1%, 35.3% and 28.6%, while 1-year progression-free survival rate was 39.1%, 20.6% and 14.3% in good, intermediate and poor LIPI groups, respectively (p < 0.001). The c-statistic and area under the curve of LIPI were 0.63 and 0.662 for OS and 1-year OS, respectively. Conclusions: Higher LIPI score is related to worse survival in advanced non-small-cell lung cancer patients treated with first-line pembrolizumab. However, based on c-statistic and area under the curve, LIPI does not represent a good prognostic survival model.

Background: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4., Methods: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy)., Results: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts., Conclusion: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients., Competing Interests: Conflict of interest statement S.B. received honoraria as a speaker at scientific events and for the advisory role from Bristol Myers Squibb (BMS), Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca and Novartis. M.B. received honoraria as a speaker at scientific events from Bristol Myers Squibb (BMS), Novartis, AstraZeneca and Pfizer and as a consultant for the advisory role from Novartis, BMS and Pfizer; she also received fees for copyright transfer from Sciclone Pharmaceuticals and research funding from Seqirus UK, Pfizer, Novartis, BMS, AstraZeneca, Roche S.p.A. and Sanofi Genzyme. R.G. received speaker fees and grant consultancies from AstraZeneca and Roche. J.G.J.V.A. reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD and Roche. A.F. received grant consultancies from Roche, Pfizer, Astellas and BMS. F.M. received grant consultancies from MSD and Takeda. R.C. received speaker fees from BMS, MSD, Takeda, Pfizer, Roche and AstraZeneca. C.G. received speaker fees/grant consultancies from AstraZeneca, BMS, Boehringer Ingelheim, Roche and MSD. M.R. received honoraria for scientific events from Roche, AstraZeneca, BMS, MSD and Boehringer Ingelheim. E.B. received speaker and travel fees from MSD, AstraZeneca, Pfizer, Helsinn, Eli Lilly, BMS, Novartis and Roche and grant consultancies from Roche and Pfizer. M.C.G. received grants from MSD, AstraZeneca, Novartis, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck, Bayer, GSK, Spectrum and Blueprint; personal fees from Eli Lilly, Boehringer Ingelheim, Otsuka Pharma, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Inivata, Takeda, Bayer, MSD, Sanofi, Seattle Genetics and Daiichi Sankyo and other financial supports from Eli Lilly, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck Serono, MSD, GSK, Spectrum and Blueprint. A.A. received grant consultancies from Takeda, MSD, BMJ, AstraZeneca, Roche and Pfizer. M.D.M. received research funding from Tesaro-GlaxoSmithKline and acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche and AstraZeneca. D.J.P. received lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche and AstraZeneca and research funding (to the institution) from MSD and BMS. M.T. received honoraria from MSD, BMS, Boehringer (BI), Takeda and AstraZeneca and research funding from AstraZeneca. A.C. received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. All the other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate., Methods: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses., Results: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate., Conclusion: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features., Competing Interests: Competing interests: AC received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. RG received speaker fees and grant consultancies by Astrazeneca and Roche. JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD and Roche. AF received grant consultancies by Roche, Pfizer, Astellas and BMS. FM received grant consultancies by MSD and Takeda. RC received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. CG received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. MR received honoraria for scientific events by Roche, Astrazeneca, BMS, MSD and Boehringer Ingelheim. EB received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; grant consultancies by Roche and Pfizer. MCG received grants from MSD, Astrazeneca, Novartis, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck, Bayer, GSK, Spectrum, Blueprint, personal fees from Eli Lilly, Boheringer, Otsuka Pharma, Astrazeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Inivata, Takeda, Bayer, MSD, Sanofi, Seattle Genetics, Daichii Sankyo, other financial supports from Eli Lilly, Astrazeneca, Novartis, BMS, Roche, Pfizer, Celgene, Tiziana Sciences, Clovis, Merck Serono, MSD, GSK, Spectrum and Blueprint. AA received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. MDM received research funding from Tesaro-GlaxoSmithKline; acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche, AstraZeneca. FP received grant consultancies by MSD and Astrazeneca. PB received grant consultancies by Astrazeneca and Boehringer-Ingelheim. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca; received research funding (to institution) from MSD, BMS. All other authors declare no competing interests. DJP is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and has received direct project funding by the NIHR Imperial Biomedical Research Centre (BRC), ITMAT Push for Impact Grant Scheme 2019. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%., Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%., Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis., Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Introduction: Atezolizumab is a humanized monoclonal antibody against PD-L1 capable of enhancing antitumor immune activity, with a demonstrated activity as single agent in patients with advanced non-small-cell lung cancer (NSCLC)., Areas Covered: This review summarizes the clinical data emerging from randomized clinical studies with atezolizumab in NSCLC and small-cell lung cancer (SCLC), focusing in particular on the efficacy and safety data regarding the combinations of atezolizumab plus chemotherapy in the IMpower studies., Expert Opinion: A significant improvement in progression-free survival and in overall survival was observed in IMpower 130 and 150 (NSCLC non-squamous) and 133 (SCLC), with an acceptable safety profile. In particular, the most common immune-related adverse events were rash (18-28% of patients), hypothyroidism (8-15%), hepatitis (5-17%), pneumonitis (2-7%), and colitis (1.5-2.3%). The safety profile of atezolizumab in combination with chemotherapy was consistent with the known adverse events related to single-agent atezolizumab and no new adverse events were observed. Ongoing studies will evaluate the role of atezolizumab in other settings (adjuvant and neoadjuvant) and in combination with chemotherapy and radiotherapy for patients with locally advanced NSCLC and the role of predictive factors (B-FAST study).

Purpose: The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab., Experimental Design: We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab., Results: Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival., Conclusion: These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer., (©2014 American Association for Cancer Research.)

Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance., Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab., Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, which were upregulated in GEO-CR cells. Furthermore, activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenous activation of MET by HGF stimulation in cetuximab-sensitive GEO and SW48 cells induced resistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-α, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-α overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells., Conclusions: These results suggest that overexpression of TGF-α through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer., (©2013 AACR.)