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BACKGROUND The early-generation ROSl tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROSl TKI with preclinical activity against ROSI fusion-positive cancers, including those with resistance mutations such as ROS1 62032. METHODS In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrec-tinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79°/o; 95°6 confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (3896; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROSl TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (5996; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 5090), and paresthesia (in 30°6), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS Repotrectinib had durable clinical activity iii patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.). [ABSTRACT FROM AUTHOR]

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32e0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46e0.98). The 5-year OS rate was 62.5% (95% CI 54.3e70.8) with alectinib and 45.5% (95% CI 33.6e57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34e1.00)] and those without [HR 0.76 (95% CI 0.45 e1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALKpositive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

BACKGROUND Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODS In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTS A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median followup was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONS Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.). [ABSTRACT FROM AUTHOR]

Cancer clinical trials enable the development of novel agents for the potential benefit of cancer patients. Enrolment in a trial offers patients the chance of superior efficacy coupled to the risk of unanticipated toxicity. For trial results to be generalisable, the data need to be collected in patients' representative of the general cancer population. Socioeconomic deprivation is associated with poor cancer outcomes. In the developed world, the gap between the most and least deprived is widening. This mini-review explores the evidence regarding socioeconomics and access to cancer trials, highlighting the underrepresentation of deprived patients, and exploring reasons for this disparity. [ABSTRACT FROM AUTHOR]

Background We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with ≥1 disease assessment was PR, n = 14; SD, n = 9; and PD, n = 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥ 3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. [ABSTRACT FROM AUTHOR]

Background In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1 -rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1 -rearranged advanced NSCLC from PROFILE 1001. Patients and methods ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily. Results Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment. Conclusions These findings serve as a new benchmark for OS in ROS1 -rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. Trial Registration Number ClinicalTrials.gov identifier NCT00585195 [ABSTRACT FROM AUTHOR]

Background Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. Patients and methods Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented. Results Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P  =   0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P  =   0.0471) and T-DM1 (P  =   0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2 - mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months. Conclusion Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy. Clinical trial registration NCT02535507. [ABSTRACT FROM AUTHOR]

Background The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK +) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n  =   64; crizotinib, n  =   58), 43 had measurable lesions (alectinib, n  =   21; crizotinib, n  =   22), and 46 had received prior radiotherapy (alectinib, n  =   25; crizotinib, n  =   21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P  <   0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK + NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840 [ABSTRACT FROM AUTHOR]

Background We report results of the first interim analysis (IA) of BRG vs CRZ in ALK TKI-naive, ALK+ NSCLC from ALTA-1L (NCT02737501). Methods This open-label, multicenter study enrolled pts with advanced ALK+ NSCLC who had ≤1 prior systemic therapy; asymptomatic CNS metastases were allowed. Pts were randomized 1:1 to BRG 180 mg QD with 7-day lead-in at 90 mg or CRZ 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed ORR, intracranial (i) ORR (iORR), and PFS (iPFS). IAs were planned at 50% and 75% of 198 expected PFS events. Results 275 pts were randomized (BRG/CRZ, n = 137/138); median age: 58/60 y. 26%/27% received prior chemotherapy for advanced disease; 29%/30% had baseline brain metastases. At data cutoff (19Feb2018), median follow-up of BRG/CRZ was 11.0/9.25 mo. With 99 PFS events, BRG met the prespecified threshold for statistical superiority vs CRZ in the primary endpoint, BIRC-assessed PFS (HR 0.49, 95% CI 0.33-0.74, log-rank P =0.0007); BRG median PFS (95% CI) was not reached (NR; NR) vs CRZ 9.8 months (9.0-12.9). Investigator-assessed PFS HR 0.45 (95% CI 0.30-0.68), log-rank P =0.0001. Confirmed ORR for BRG was 71% (62-78) vs CRZ 60% (51-68). In pts with any iCNS disease (BRG/CRZ, n = 43/47), confirmed iORR was 67% (51-81) vs 17% (8-31), P <0.0001. BRG median iPFS was NR (11 mo-NR) vs CRZ 6 mo (4-9); HR 0.27 (95% CI 0.13-0.54); log-rank P <0.0001. In pts with measurable iCNS disease (BRG/CRZ, n = 18/21), confirmed iORR was BRG 78% (52-94) vs CRZ 29% (11-52); P =0.0028. Most common grade ≥3 TEAEs for BRG were increased CPK (16.2%) and lipase (13.2%), hypertension (9.6%), and for CRZ were increased ALT (9.5%), AST (5.8%), and lipase (5.1%). Any grade ILD/pneumonitis (BRG/CRZ): 3.7%/2.2%; discontinuations due to AE: 11.8%/8.8%. Conclusions BRG showed a statistically and clinically significant improvement in PFS vs CRZ in ALK inhibitor-naive ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

Objectives: The ALTA-1L phase 3 open-label trial demonstrated increased progression-free survival (PFS) with brigatinib versus crizotinib in patients with anaplastic lymphoma kinase-positive (ALK-positive) locally advanced or metastatic non-small cell lung cancer (NSCLC) previously untreated with ALK-targeted therapy. This post-hoc analysis of data from the ALTA-1L trial used the quality-adjusted (QA) time without symptoms of disease or toxicity (Q-TWiST) methodology to compare the QA survival benefit of brigatinib versus crizotinib in this patient population., Patients and Methods: The Q-TWiST analysis was performed using final (January 29, 2021) individual patient-level blinded independent review committee (BIRC)- and investigator-assessed survival data for brigatinib (n = 137) and crizotinib (n = 138) in adult patients (N = 275) with ALK-positive locally advanced or metastatic NSCLC previously untreated with ALK-targeted therapy. Q-TWiST was compared between the two treatments. Subgroup analyses were performed in patients stratified by various clinicopathological characteristics, including presence or absence of brain metastases at baseline., Results: Brigatinib was associated with significantly longer time without symptoms of disease or toxicity (P < 0.001) than crizotinib, with significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 28.2 [1.2] versus 25.1 [1.1], P = 0.045; investigator-assessed, 28.5 [1.2] versus 24.8 [1.1], P = 0.018). Relative gains in Q-TWiST with brigatinib compared to crizotinib were clinically meaningful (BIRC-assessed, 10.4%; investigator-assessed, 12.3%). Patients with brain metastases at baseline receiving brigatinib had significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 29.0 [1.9] versus 19.0 [1.9], P = 0.0001) than those receiving crizotinib., Conclusion: First-line brigatinib treatment was associated with significant and clinically meaningful gains in Q-TWiST compared to crizotinib in patients with ALK-positive locally advanced or metastatic NSCLC, supporting the results of the ALTA-1L trial and brigatinib as a safe and effective first-line treatment for ALK-positive NSCLC., 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 © 2023. Published by Elsevier B.V.)

Objectives: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study., Methods: ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg., Results: NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification., Conclusions: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients., Trial Registration: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516., (Copyright © 2021. Published by Elsevier B.V.)

Background: Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs., Patients and Methods: In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1., Results: Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5)., Conclusions: Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy., Competing Interests: Disclosure EF has served on advisory boards for AbbVie, Bayer, Blueprint Medicines, GlaxoSmithKline, Guardant Health, Janssen, Merck KGaA, and Samsung; speakers' bureaus for Medscape, prIME Oncology, and TouchIME; advisory boards and speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and received research funding from Fundación Merck Salud and Grant for Oncology Innovation; independent member of the board for Grifols. ATS has served as a compensated consultant or received honoraria from Achilles, Archer, Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, and TP Therapeutics; received institutional research funding from Ariad, Ignyta, Novartis, Pfizer, Roche-Genentech, and TP Therapeutics; received travel support from Genentech and Pfizer; and is currently an employee of Novartis. AB has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Roche, and Takeda. DRC has received honoraria from AbbVie, Achilles Therapeutics, Apollomics, Archer, Arrys/Kyn, AstraZeneca, BeyondSpring Pharmaceuticals, Biothera, Blueprint Medicines, Bristol-Myers Squibb, CBT Pharmaceuticals, Daiichi-Sankyo, Elevation, EMD Serono, G1 Therapeutics, Hansoh, Helsinn Therapeutics, Hengrui Pharmaceutical, Inivata, Lilly, Medtronic, Regeneron, Ribon Therapeutics, Roche, and Takeda; and received research funding from Takeda. BJS has served as a consultant or on advisory boards for Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche-Genentech. JRB has served as a consultant for Astra Zeneca and Pfizer; has served on advisory boards for Bayer and Kura; and received institutional research funding from Bristol-Myers Squibb, unrelated to this work. TMB reports employment by Tennessee Oncology; has served as a consultant/advisor for Bayer, Blueprint Medicines, Exelixis, Foundation Medicine, Guardant Health, Ignyta, Loxo Oncology, Moderna Therapeutics, and Pfizer; has served on speakers' bureaus for Bayer, Bristol-Myers Squibb, and Lilly; received research funding from AbbVie, Aileron Therapeutics, Amgen, ARMO BioSciences, Astellas Pharma, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Clovis Oncology, Daiichi-Sankyo, Deciphera, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Janssen, Karyopharm Therapeutics, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, MabVax, MedImmune, Medpacto, Inc., Merck, Merrimack, Millennium, Mirati Therapeutics, Moderna Therapeutics, Novartis, Onyx, Peleton, Pfizer, Phosplatin Therapeutics, Principia Biopharma, Roche, Sanofi, Stemline Therapeutics, Takeda, and Top Alliance BioSciences; and compensation for travel, accommodations, and expenses from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Sysmex. SP has received education grants, provided consultation, attended advisory boards, and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi-Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, and Vaccibody, from whom she has received honoraria (all fees to institution). FT, AA report employment by Pfizer. HT, GP, RW report employment by Pfizer and are Pfizer shareholders. BB reports sponsored research at Gustave Roussy Cancer Center, AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, and Tolero Pharmaceuticals. Data sharing Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction., Patients and Methods: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation., Results: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2)., Conclusions: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes., Patients and Methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively., Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17)., Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.