Search

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK -positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up., Methods: Two hundred ninety-six patients with ALK -positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses., Results: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment., Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK -positive NSCLC and set a new benchmark for targeted therapies in cancer.

Background: PERLA (NCT04581824) compared efficacy and safety of dostarlimab (DCT) or pembrolizumab (PCT) plus chemotherapy as first-line treatment for metastatic non-small cell lung cancer. Here, we report patient-reported outcomes (PROs; exploratory analysis) from PERLA., Methods: Patients were randomized 1:1 to receive DCT or PCT every 3 weeks (Q3W) for ≤ 35 cycles [C]. PROs (EORTC QLQ-C30 and QLQ-LC13, PRO-CTCAE, FACT-GP5) were collected at baseline, Q3W until C4, Q9W until C16, Q12W until end of treatment and at 30-day safety follow-up. Change from baseline and time to deterioration (TTD) in QLQ-C30 and QLQ-LC13 were analyzed using longitudinal mixed models and Kaplan-Meier estimators, respectively., Results: The PRO (DCT/PCT) datasets included 102/99 patients for QLQ-C30, 96/90 for QLQ-LC13, 96/88 for PRO-CTCAE, and 95/87 for FACT-GP5. Completion rates were > 80 % to C4, then decreased in both arms. For QLQ-C30 and QLQ-LC13, most patients reported stable/improved responses at C13 (∼ 9 months on treatment), with similar responses between arms except more patients reported improvements in dyspnea (QLQ-C30: 36.4 % vs 13.0 %; QLQ-LC13: 40.6 % vs 25.0 %) and chest pain (QLQ-LC13: 34.4 % vs 10.0 %) with DCT vs PCT. TTD per QLQ-C30 and QLQ-LC13 were similar between arms, although TTD in dyspnea was longer with DCT vs PCT (QLQ-LC13: 4.24 vs 1.54 months; p = 0.0168). Most patients in both arms reported that adverse events occurred occasionally/rarely/never with moderate/mild severity. Overall, patients reported little/no bother from treatment side effects., Conclusions: DCT maintained health-related quality of life similarly to PCT and was well tolerated, supporting the PERLA primary results and dostarlimab use in future regimens., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Reck has had an advisory role for Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Novartis, Pfizer, Regeneron, Roche, Samsun Bioepsis, and Sanofi. Ana Laura Ortega Granados is an employee of the Servicio Andaluz de Salud and has had an advisory role for Roche, Bristol Myers Squibb, and Merck Sharp Dohme. Filippo de Marinis has had an advisory role for AstraZeneca, Roche, Novartis, Merck, BMS, and MSD. Oren Meyers is an employee of and holds financial equities in GSK. Qin Shen is an employee of and holds financial equities in GSK. Lillian Cho is an employee of and holds financial equities in GSK. Neda Stjepanovic is an employee of and holds financial equities in GSK. Susan Boklage is an employee of and holds financial equities in GSK., (Copyright © 2024. Published by Elsevier Ltd.)

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK . To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR -mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR -mutated NSCLC showed the relevant PFS improvement. In the ALK -positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK -positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK . In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

Purpose: Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR -mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837)., Methods: Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS., Results: Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients., Conclusion: Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Purpose: The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported., Methods: Patients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m 2 intravenous infusion on day 1) in 21-day cycles. Primary end point was overall survival (OS). Key secondary end points were investigator-assessed progression-free survival (PFS), objective response rate, patient-reported symptom assessment, and safety., Results: In the intention-to-treat population (SG, n = 299; docetaxel, n = 304), 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary end point was not met. There was a numerical OS improvement for SG versus docetaxel (median, 11.1 v 9.8 months; hazard ratio [HR], 0.84 [95% CI, 0.68 to 1.04]; one-sided P = .0534), consistent across squamous and nonsquamous histologies. Median PFS was 4.1 versus 3.9 months (HR, 0.92 [95% CI, 0.77 to 1.11]). An OS benefit was observed for SG (n = 192) versus docetaxel (n = 191) in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen (3.5-month median OS increase; HR, 0.75 [95% CI, 0.58 to 0.97]); this was consistent across histologies. Among patients receiving SG and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs), respectively; 1.4% and 1.0%, respectively, had TRAEs leading to death., Conclusion: Although statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

Non-small cell lung cancer (NSCLC) poses a significant challenge in clinical oncology, necessitating continual refinement of treatment approaches in stages II and III. Recent advancements have highlighted the potential of neoadjuvant therapy in optimising patient outcomes. Biomarker testing guides neoadjuvant therapy decisions, including epidermal growth factor receptor (EGFR) mutation and programmed death-ligand 1 (PD-L1) expression testing. Neoadjuvant therapy aims to improve oncological outcomes by treating micrometastatic disease and assessing tumour response before surgery. Disease-free survival is a surrogate endpoint for overall survival in both neoadjuvant and adjuvant settings. Multidisciplinary collaboration is crucial for individualised treatment planning and optimising patient care. The management of NSCLC requires a comprehensive approach, integrating expertise across disciplines and tailoring treatment strategies to individual patient needs. Neoadjuvant therapy shows promise in improving long-term outcomes, with biomarker testing guiding treatment decisions. Challenges such as defining borderline resectability and differentiating pseudoprogression highlight the need for ongoing research and collaboration.

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.)

Shirish Gadgeel,1 Alice T Shaw,2 Fabrice Barlesi,3 Lucio Crino,4 James CH Yang,5 Anne-Marie Dingemans,6 Dong-Wan Kim,7 Filippo de Marinis,8 Mathias Schulz,8 Shiyao Liu,9 Ravindra Gupta,9 Vlatka Smoljanovic,10 Sai-Hong Ignatius Ou11 1Department of Internal Medicine, Division of Hematology and Oncology, The University of Michigan, Ann Arbor, MI 48109, USA; 2Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA; 3Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille 13005, France; 4Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl I.R.C.C.S., Meldola, FC 47014, Italy; 5National Taiwan University Hospital and National Taiwan University Cancer Centre, Taipei City, Taiwan; 6Department of Pulmonology, Maastricht University Medical Centre, Maastricht 6229 HX, The Netherlands; 7Department of Internal Medicine, Seoul National University Hospital, Jongno-Gu, Seoul 03080, South Korea; 8Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan 20146, Italy; 9Genentech Inc., South San Francisco, CA, USA; 10F. Hoffmann-La Roche Ltd., Basel CH-4070, Switzerland; 11Division of Hematology-Medical Oncology, Department of Internal Medicine, University of California, Irvine School of Medicine, Orange, CA 92617, USACorrespondence: Sai-Hong Ignatius OuUniversity of California, Irvine School of Medicine, 1001 Health Sciences Road, Irvine, Orange, CA 92617, USATel +1 714 456 8104Email siou@uci.eduIntroduction: Alectinib is a highly selective and potent ALK inhibitor, approved for the treatment of patients with metastatic ALK+ NSCLC based on results from the Phase II global NP28673 (NCT01801111) and North American NP28761 (NCT01871805) studies.Methods: This exploratory analysis of two Phase II studies of alectinib (NP28673/NP28761) investigated time to systemic response (TTR) and time to central nervous system (CNS) response (TTCR) in patients with previously treated advanced anaplastic lymphoma kinase fusion gene-positive (ALK+) non-small-cell lung cancer. Patients (n=225) received 600 mg oral alectinib twice daily and had scans every 6/8 weeks (NP28673/NP28761).Results: For NP28673 and NP28761, respectively: median follow-up was 21.3 months/17.0 months; most responders (72.6%/82.9%) responded by the first disease assessment; median TTR was 8 weeks (95% confidence interval [CI]: 8.00–8.14)/6 weeks (95% CI: 5.86–6.14); median TTCR in responders with measurable baseline CNS disease was 8 weeks (95% CI: 7.86–10.29)/6 weeks (95% CI: 5.71–not evaluable). Similar results were observed regardless of measurable/non-measurable disease.Discussion: These data suggest that alectinib achieves a rapid response in patients, both systemically and in the CNS.Keywords: alectinib, non-small-cell lung cancer, NP28673, NP28761, time to response

Third-generation EGFR tyrosine kinase inhibitor (TKIs) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations, with improved long-term outcomes compared to first-generation TKIs. Nevertheless, disease progression inevitably occurs, limiting osimertinib long-term efficacy. Indeed, the molecular biology underlying acquired resistance to first-line osimertinib is multifaceted and includes the emergence of on-target and off-target alterations. EGFR-C797S mutation represents the most frequent mechanism of on-target resistance and hinders drug binding to the target site. EGFR-independent resistance includes the activation of alternative signaling pathways, such as MET amplification and HER2 mutations, and histological transformation. In this setting, chemotherapy is the current therapeutic option, with modest clinical outcomes. Therefore, the development of novel therapeutic strategies to overcome resistance to osimertinib is a major challenge. In this setting, fourth-generation TKIs are emerging as an interesting therapeutic option to overcome on-target resistance. Preclinical drug development has led to the discovery of thiazole-amid inhibitors, which activity is mediated by the allosteric inhibition of EGFR, resulting in high specificity towards mutant-EGFR. Early phase 1/2 clinical trials are ongoing to elucidate their activity also in the clinical setting. Aim of this review is to provide a state-of-the-art analysis on preclinical development of fourth-generation EGFR-TKIs and promising preliminary clinical data., 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Actionable driver mutations account for 40-50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes. Methods: We retrospectively evaluated the prevalence and patterns of concurrent driver genomic alterations in a large series of NSCLCs to investigate their association with clinicopathological characteristics, to assess the prognosis of patients whose tumor harbors concurrent alterations in the genes of interest and to explore their potential therapeutic implications. Results: Co-occurring driver alterations were identified in 26 out of 1520 patients with at least one gene alteration (1.7%). Within these cases, the incidence of concurrent actionable gene alterations was 39% (0.7% of the overall cohort). Among compound actionable gene mutations, EGFR was the most frequently involved gene (70%). The most frequent association was EGFR mutations with ROS1 rearrangement. Front-line targeted treatments were the preferred approach in patients with compound actionable mutations, with dismal median PFS observed (6 months). Conclusions: Advances in genomic profiling technologies are facilitating the identification of concurrent mutations. In patients with concurrent actionable gene alterations, integrated molecular and clinical data should be used to guide treatment decisions, always considering rebiopsy at the moment of disease progression.

Background: Platinum-based chemotherapy is the current standard treatment option in patients with EGFR -mutant non-small-cell lung cancer (NSCLC) who progress on osimertinib. However, outcomes with chemotherapy are dismal, and the treatment of central nervous system (CNS) disease is an unmet need in this setting., Methods: Patients with EGFR -mutant NSCLC who were candidates to receive osimertinib in the metastatic setting at our Center from 2015 to 2022 were retrospectively evaluated to identify patients who received standard platinum-based chemotherapy post-osimertinib. Data were collected on treatment outcomes, with a focus on brain metastases and progression patterns., Results: A total of 220 patients received indication for osimertinib in the study period; n = 176 had adequate follow-up data. Overall, n = 117 patients experienced disease progression on osimertinib. The median time to osimertinib progressive disease (PD) was 15 months (95% confidence interval CI 13-18). Of them, 51 patients (45%) had no access to further treatments. Of the remaining patients, n = 8 received experimental treatments, and n = 55 received standard platinum-based chemotherapy and were considered for this study. Median duration of chemotherapy was 3 months (95% CI 2-5); the best responses among 53 evaluable patients were observed as follows: 15% partial response/complete response (PR/CR), 40% stable disease (SD), 45% PD. Median progression-free survival (PFS) and overall survival (OS) were 3 (95% CI 2-5) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow-up brain radiologic assessments, and n = 23 had brain metastases at the start of chemotherapy. With a median follow-up of 13 months, intracranial PD occurred in 47% patients, being the first site of PD in 59% of cases. The median time for intracranial (IC) PD was 2 months (95% CI 2-7). IC PD occurred as oligometastatic in 29%, whereas in 71% of cases, it was associated with systemic PD., Conclusions: Access to subsequent treatments and CNS progression are confirmed unmet needs in EGFR -mutant NSCLC patients. Clinical and CNS-specific outcomes in patients receiving standard chemotherapy after the failure of osimertinib are dismal. Novel upfront treatment options with demonstrated prolonged PFS and better CNS outcomes may help address this important issue.

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile., Competing Interests: I. Attili received consulting fees from Bristol-Myers Squibb outside the submitted work. F. de Marinis received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery and Roche outside the submitted work. A. Passaro reports personal fees, as a speaker bureau or advisor, for AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Merck Sharp & Dohme, Janssen, Novartis, Pfizer and Roche Genentech outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports., (© 2024. The Author(s).)

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.

Background: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation., Materials and Methods: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction., Results: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response., Conclusions: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice., Clinical Trial Registration: Eudract No. 2019-001146-17, NCT04028050., (© The Author(s) 2024. Published by Oxford University Press.)

Medical treatment has changed drastically in recent years, especially for advanced stages of non-small-cell lung cancer (NSCLC), for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. This single-center retrospective study aimed to analyze the outcome predictors, the surrogate outcomes, and the patient-reported outcomes after neoadjuvant immunotherapy for initially unresectable NSCLC. Patients affected by an initially unresectable NSCLC and identified between March 2014 and December 2021 who received immunotherapy alone or in combination with platinum-based chemotherapy and/or radiotherapy were collected. Overall survival (OS) and disease-free survival (DFS) were estimated according to the Kaplan-Meier method. Patient-reported outcomes were recorded using the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QoL) Group questionnaire-Lung Cancer 29 Module to compare differences in symptoms and QoL at two different times, 30 days and 1 year after surgery. Surgical, pathological records, and patient-reported outcomes (at 30 days and 1 year after surgery) were reviewed. Complete pathological remission was achieved in 7 patients (36.8%) and major pathological remission in 3 patients (15.7%). The median overall survival in the study group is 19 months (range: 2-57.4). Of 19 patients, 16 (84.2%) are alive to date, of which 2 (10.5%) have a local recurrence. At 30 days from surgery, the main symptoms reported by EORTC Module were coughing, shortness of breath, the side effect of treatment, fear of progression, and surgery-related problems. Induction immunotherapy with or without chemotherapy can be considered for unresectable locally advanced NSCLC, and after the downstaging, the possibility of surgery could be re-evaluated in a multidisciplinary setting with high rates of R0 resection. In this selected and highly motivated group of patients, the QoL and symptoms after salvage surgeries are acceptable and even better than those reported in the literature., (© 2023. Italian Society of Surgery (SIC).)

Background: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK -positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK -positive NSCLC are lacking., Methods: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK -positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety., Results: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed., Conclusions: Among patients with resected ALK -positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.)., (Copyright © 2024 Massachusetts Medical Society.)

Uncommon (ucEGFRmuts) and rare epidermal growth factor receptor ( EGFR ) mutations account for 10-15% of diagnosed cases and consist of a heterogeneous group represented by several clusters within exons 18-21 (e.g., exon 18 point mutations, exon 21 L861X, exon 20 S768I), as well as exon 20 insertions (Ex20ins). Their incidence is under molecular and clinical investigation following recent findings that reported an increase of sensitivity and specificity of next-generation sequencing (NGS) methods. Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of EGFR -mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion-mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients.

Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports. • Phase III trial of sitra + nivo compared with docetaxel in patients with advanced nonsquamous NSCLC. • The study evaluated whether CPI resistance can be overcome in patients treated with platinum-based chemotherapy and CPI. • The primary endpoint of improved OS with sitra + nivo versus docetaxel was not met. • The safety profiles of both regimens were consistent with previous reports, with no new safety signals. [ABSTRACT FROM AUTHOR]