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Introduction: In the AEGEAN trial, neoadjuvant durvalumab plus platinum-based chemotherapy (D+CT) followed by adjuvant durvalumab, versus neoadjuvant chemotherapy alone, significantly improved pathological complete response (pCR) rate and event-free survival (EFS) in patients with resectable NSCLC. In the PACIFIC trial, consolidation durvalumab significantly improved progression-free (PFS) and overall survival (OS) for patients with unresectable stage III NSCLC after chemoradiotherapy. Strong pathological and clinical outcomes with chemoimmunotherapy have generated interest in its use to enable patients with borderline-resectable NSCLC to undergo surgery. Additionally, for patients initially deemed resectable but who later become unresectable/inoperable during neoadjuvant treatment, consolidation immunotherapy after chemoradiotherapy should be explored., Patients and Methods: MDT-BRIDGE (NCT05925530) is a multicenter, phase II, non-randomized study in ∼140 patients with EGFR/ALK wild-type, stage IIB-IIIB (N2) NSCLC. Following baseline multidisciplinary team (MDT) assessment to determine resectable/borderline-resectable status, all patients receive 2 cycles of neoadjuvant D+CT every 3 weeks, followed by MDT reassessment of resectability. Patients deemed resectable receive 1-2 additional cycles of D+CT followed by surgery (Cohort 1). Patients deemed unresectable receive standard-of-care chemoradiotherapy (Cohort 2). Cohort 1 patients who become ineligible for surgery can enter Cohort 2. Following surgery or chemoradiotherapy, patients receive adjuvant or consolidation durvalumab for 1 year. The primary endpoint is resection rate in all patients. Additional endpoints include resection rates by baseline resectable/borderline-resectable status, resection outcomes, EFS/PFS, OS, pCR rate, circulating tumor DNA dynamics pre- and post-surgery (including correlation with clinical outcomes), and safety., Conclusion: Enrollment began in February 2024; primary completion is anticipated in April 2026., Competing Interests: Disclosure Martin Reck reports honoraria for lectures and consultation fees from AstraZeneca, Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Roche, and Regeneron. Ernest Nadal reports research grants from Roche, Pfizer, Merck Serono, and Bristol Myers Squibb; consultation fees from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer Ingelheim, AstraZeneca, Qiagen, Pierre Fabre, Takeda, Sanofi, and Bayer, and paid expert testimony for Apollomics, Roche, and Merck Sharp & Dohme. Nicolas Girard reports research grants/support from AbbVie, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Hoffmann-La Roche, Janssen, LEO Pharma, Lilly, Merk Serono, Merck Sharp & Dohme, Novartis, Sanofi, and Sivan; consultative services for AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Ipsen, Hoffmann-La Roche, Janssen, LEO Pharma, Lilly, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, and Takeda; and employment of a family member with AstraZeneca. Andrea R. Filippi reports consultation fees from AstraZeneca, Roche, and Radiomics; an institutional research grant from AstraZeneca, being a principal investigator for AstraZeneca and being a co-investigator in clinical trials sponsored by Roche and Merck Sharp & Dohme. Linda W. Martin reports honoraria for speakers bureau participation from Ethicon and Genentech, and consultation fees for steering committee participation from OnTarget Laboratories. Carl M. Gay reports honoraria from AstraZeneca, BeiGene, MJH Healthcare, OncLive, PeerView, and Targeted Healthcare, and consultation fees from AstraZeneca, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi-Sankyo, G1 Therapeutics, Jazz Pharmaceuticals, Kisoji Biotechnology, Monte Rosa Therapeutics, Roche/Genentech, and STCube. Cordula Petersen reports no potential conflicts of interest. Davina Gale reports full employment, stock ownership or options, and a patent pending with AstraZeneca. Ugochinyere Emeribe reports full employment and stock ownership or options with AstraZeneca. Nefeli Georgoulia reports full employment and stock ownership or options with AstraZeneca. Ignacio E. Diaz Perez reports full employment and stock ownership or options with AstraZeneca. Jonathan Spicer reports honoraria from Bristol Myers Squibb, Merck, AstraZeneca, Roche, Amgen, Pfizer, Daiichi, and Eisai, consultation fees from Bristol Myers Squibb, Merck, and AstraZeneca, and institutional grants from Bristol Myers Squibb, Merck, AstraZeneca, Roche, CLS Therapeutics, and Protalix Biotherapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population., Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete)., Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea., Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated., Funding: Merck (CrossRef Funder ID: 10.13039/100009945)., Competing Interests: Declaration of interests Y-LW reports receiving institute grants from AstraZeneca, Bristol Myers Squibb, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Merck, and Roche; and speaker fees from AstraZeneca, Eli Lilly, Hengrui, Pfizer, Roche, and Sanofi. VG reports receiving personal fees for advisory board membership from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, and Olema Oncology; speaker fees from Amgen, AstraZeneca, Eli Lilly, Exact Sciences, Gilead, GSK, and Novartis; fees for expert testimony for Eli Lilly; and travel support from Gilead, AstraZeneca, and PharmaMar. PJV reports receiving personal fees for advisory board membership from Amgen, AstraZeneca, BeiGene, Ipsen, MSD, Novartis, Pfizer, and Roche. MWi reports receiving personal advisory board fees, consulting fees, speaker fees, and institute grants from AstraZeneca. CKL reports receiving research grants from AstraZeneca and Boehringer Ingelheim; honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, Pfizer, Roche, and Zuellig Pharma; travel support from AstraZeneca, Boehringer Ingelheim, Merck, MSD, Novartis, Pfizer, and Roche; and personal fees for advisory board membership from AstraZeneca, Janssen, MSD, Novartis, Pfizer, and Roche. JM reports receiving advisory board fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Novartis, Merck, Daiichi Sankyo, and MSD, and research funding to his institution from Roche, AstraZeneca, and Pierre Fabre. LMT reports receiving advisory board fees from AstraZeneca, Janssen, Merck, Novartis, Pfizer, and Roche; personal honoraria fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and travel support from AstraZeneca, Merck, Novartis, Pfizer, and Roche. HH reports receiving honoraria fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, Sysmex Corporation, 3H Medi Solution, Chugai Pharmaceutical, Pfizer, Novartis, Merck Biopharma Co, Tokyo, Japan, an affiliate of Merck, Amgen, Daiichi Sankyo/UCB Japan, Takeda, and MSD; research funding from IQVIA, Syneos Health Clinical, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho Pharmaceutical, Bristol Myers Squibb, Janssen, CMIC, Pfizer R&D, LabCorp, Kobayashi Pharmaceutical, Pfizer, Eisai, EP-CRSU, Shionogi & Co, Otsuka Pharmaceutical, GSK, Sanofi, Chugai Pharmaceutical, Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, and Bayer; and financial support for the present manuscript from Guardant Health. PLC reports receiving advisory board fees from AstraZeneca, Merck, and Pfizer, and honoraria fees from AstraZeneca. JR reports receiving personal honoraria from Bristol Myers Squibb, speaker fees (to their institution) from Merck, and advisory board fees (to their institution) from Merck. GF reports receiving personal fees for speaker engagements with AstraZeneca, Bristol Myers Squibb, and MSD, and travel support from Roche. TK reports receiving honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; receiving research funding for their institution from AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis, Pfizer, Regeneron, Takeda, and TurningPoint; receiving advisory board fees from AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck, MSD, Novartis, and Pfizer; and their spouse as an employee of Eli Lilly. EN reports receiving research funding from Roche, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Bristol Myers Squibb; consulting fees from Roche, Bristol Myers Squibb, MSD, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Pierre Fabre, Qiagen, and Bayer; personal honoraria for lectures from Roche, Bristol Myers Squibb, MSD, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Qiagen, Mirati, and Bayer; travel support from Takeda, MSD, AstraZeneca, and Roche; and fees for participation in data safety meetings from Apollomics. HSH reports receiving research grants for their institution from AstraZeneca, Merck, Janssen, Novartis, and Boehringer Ingelheim; honoraria and fees for lectures and advisory board meetings from AstraZeneca, MSD, Novartis, Pfizer, Roche, and Janssen; and travel support from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche. EFS reports receiving advisory or consultancy fees to their institution from Eli Lilly, AstraZeneca, MSD, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, and Daiichi Sankyo; personal speaker fees from Boehringer Ingelheim; and advisory board fees from Merck and Daiichi Sankyo. MWe reports holding a consulting or advisory role for Bristol Myers Squibb, Novartis, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, and ImCheck therapeutics; honoraria fees from Eli Lilly, Boehringer Ingelheim, SYNLAB, Janssen, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, GWT, Amgen, and Novartis; travel support from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck; and research funding to his institution from Roche. DT reports receiving consulting fees for their institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GSK, Merck, Novartis, Roche, Pfizer, and Takeda; research funding from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer; and speaker fees for their institution from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda. MM reports receiving research funding from Boehringer Ingelheim and Eli Lilly; personal honoraria fees from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; and other clinical trial support from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Kissei, Taiho, and Novartis. AO’B, SA, BMP, CS, DJ, RS, BE-L, and NK report being employees of Merck. KB reports being an employee of Merck at the time of the study and manuscript preparation. KG reports being an employee of EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck. XL reports receiving consulting fees from EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen Oncology, Daiichi Sankyo, Blueprint Medicines, Sensei Biotherapeutics, AbbVie, Arrivent, and Regeneron; travel support from Spectrum Pharmaceuticals and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and research funding to their institution from Eli Lilly, Boehringer Ingelheim, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Regeneron. TMK reports receiving grants for their institution from AstraZeneca; consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda, and Yuhan; honoraria for lectures from AstraZeneca, IMBDx, Janssen, Takeda, and Yuhan; advisory board fees from AstraZeneca, Janssen, Regeneron, and Takeda; and clinical trial funding to their institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Roche/Genentech, Hanmi, Genmab, Janssen, Novartis, RAPT Therapeutics, Regeneron, Sanofi, Takeda, and Yuhan. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP., Methods: ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m 2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS)., Results: During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3-10.8 months). Median PFS was 9.8 months (95% CI: 6.6-10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment., Conclusions: This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials., Trial Registration: EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016., (© 2024. The Author(s).)

What Is This Summary About?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI ® ) and binimetinib (MEKTOVI ® ). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer., What Were the Results?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting., What Do the Results Mean?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Background: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients., Methods: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety., Results: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%)., Conclusions: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.)., (Copyright © 2023 Massachusetts Medical Society.)

The discovery of oncogenic driver mutations led to the development of targeted therapies with non-small cell lung cancer (NSCLC) being a paradigm for precision medicine in this setting. Nowadays, the number of clinical trials focusing on targeted therapies for uncommon drivers is growing exponentially, emphasizing the medical need for these patients. Unfortunately, similar to what is observed with most targeted therapies directed against a driver oncogene, the clinical response is almost always temporary and acquired resistance to these drugs invariably emerges. Here, we review the biology of infrequent genomic actionable alterations in NSCLC as well as the current and emerging therapeutic options for these patients. Mechanisms leading to acquired drug resistance and future challenges in the field are also discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In EGFR mutation-positive NSCLC, dual EGFR/VEGFR inhibition compared to EGFR alone increases anti-tumor efficacy. The Phase III RELAY trial demonstrated superior PFS for ramucirumab plus erlotinib (RAM + ERL) over placebo plus erlotinib (PBO + ERL) (HR 0.591 [95% CI 0.461-0.760], p<0.0001). EGFR mutated NSCLC is less prevalent in Western versus Asian patients. This prespecified analysis evaluates efficacy and safety of RAM + ERL in EU and US patients enrolled in RELAY., Patients and Methods: Patients were randomized 1:1 to ERL + RAM (10 mg/kg IV) or PBO Q2W. Treatment continued until unacceptable toxicity or progressive disease. Patients were stratified by geographic region (East Asia vs "other" [EU/US and Canada (EU/US)]). Objectives included PFS, ORR, DoR, OS, PFS2, safety and biomarker analysis., Results: EU/US subset included 113/449 (25.9%) patients (58 RAM + ERL, 55 PBO + ERL). RAM + ERL improved PFS (20.6 vs 10.9 months, HR 0.605 [95% CI: 0.362-1.010]). ORR and DCR were similar, but median DoR was longer with RAM + ERL (18.0 vs 10.1 months, HR 0.527 [95% CI: 0.296-0.939]). OS and PFS2 were immature at data cut-off (censoring rates 81.0-81.8% and 67.3-79.3%, respectively). Most commonly reported Grade ≥3 TEAE for RAM + ERL was hypertension (17 [29.8%]) and for PBO + ERL, dermatitis acneiform (5 [9.1%])., Conclusion: EU/US subset analysis showed improved efficacy outcomes for RAM + ERL and a safety profile consistent with the overall population. Ramucirumab is a safe and effective addition to standard-of-care EGFR-TKI for EGFR mutation-positive metastatic NSCLC., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC., Methods: This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m 2 ) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients., Findings: Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4-28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9-87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%])., Interpretation: Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable., Funding: Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC., Methods: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models., Results: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8 + infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion., Conclusions: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E. Nadal has received honoraria for participating in advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim and AstraZeneca. E. Nadal has received research funding from Roche and Pfizer.J. Bosch-Barrera serves on advisory boards and/or accepted honoraria for giving lectures from Bristol Myers-Squibb (BMS), Roche, Merck Sharp & Dohme (MSD), AstraZeneca, Novartis and Boehringer-Ingelheim. J. Bosch-Barrera has also received grants for research from Pfizer and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Around 40% of newly diagnosed lung cancer patients are Stage IV, where the improvement of survival and reduction of disease-related adverse events is the main goal for oncologists. In this scenario, we present preclinical evidence supporting the use of ABTL0812 in combination with chemotherapy for treating advanced and metastatic Nonsmall cell lung adenocarcinomas (NSCLC) and squamous carcinomas. ABTL0812 is a new chemical entity, currently in Phase 1b/2a clinical trial for advanced squamous NSCLC in combination with paclitaxel and carboplatin (P/C), after successfully completing the first-in-human trial where it showed an excellent safety profile and signs of efficacy. We show here that ABTL0812 inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. Furthermore, treatment with ABTL0812 also induces AMPK activation and ROS accumulation. Moreover, combination of ABTL0812 with chemotherapy markedly increases the therapeutic effect of chemotherapy without increasing toxicity. We further show that combination of ABTL0812 and chemotherapy induces nonapoptotic cell death mediated by TRIB3 activation and autophagy induction. We also present preliminary clinical data indicating that TRIB3 could serve as a potential novel pharmacodynamic biomarker to monitor ABTL0812 activity administered alone or in combination with chemotherapy in squamous NSCLC patients. The safety profile of ABTL0812 and its good synergy with chemotherapy potentiate the therapeutic potential of current lines of treatment based on chemotherapy regimens, arising as a promising option for improving these patients therapeutic expectancy., (© 2020 UICC.)

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.

Background: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC., Methods: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up., Findings: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group., Interpretation: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC., Funding: Eli Lilly., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial., Material and Methods: NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached., Results and Conclusion: As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance., Methods: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C., Results: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs., Conclusion: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Introduction: We present the treatment rationale and study design for the RELAY study (NCT02411448 ). This phase Ib/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non-small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation., Patients and Methods: The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase Ib), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose-limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life., Conclusion: Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.

Purpose: Although concurrent chemotherapy and radiation is the standard approach for good risk unresectable stage III non-small cell lung cancer (NSCLC) patients, there is no optimal concurrent chemotherapy regimen. Administration of chemotherapy at full dose with maximal activity against local and micrometastatic disease is highly desirable. This study tested the feasibility of 3 cycles of full dose cisplatin and pemetrexed concurrent with definitive thoracic radiotherapy followed by consolidation pemetrexed, without the dose-limiting toxicity (DLT) exceeding 33% of the patients., Methods: Patients with unresectable stage III NSCLC, good performance status and no serious comorbidity were eligible. Patients received thoracic radiation to a dose of 66 Gy concurrently with three 21-day cycles of pemetrexed 500 mg/m(2), and cisplatin at escalating doses from 60 to 75 mg/m(2). Consolidation chemotherapy of pemetrexed 500 mg/m(2) was provided for 3 more 21-day cycles. Cisplatin doses were escalated as far as no more than 1/3 of the patients in a level developing dose limiting toxicities (DLT)., Results: Fifteen eligible patients were enrolled: nine in the first dose level and 3 in the second and third dose levels respectively. Two out of 9 patients in the first dose level experienced DLT (grade 3 esophagitis resulting in delay in treatment administration). The major serious acute toxicities were esophagitis (40%) and febrile neutropenia (20%). With a median follow up time of 22 months, median time to progression and overall survival has not been reached. The rate of survival at 24 months was 57.5% (95% CI: 27.5-87.4%) of the patients., Conclusions: Three systemic dose levels of pemetrexed and cisplatin could be administered concurrently with radiotherapy. The rate of survival at 24 months was encouraging., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12 Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum