A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small cell lung cancer.

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.

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC). METHODS: In this ongoing, open-label, single-arm, phase II study, patients with BRAFV600E-mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety. RESULTS: At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with BRAFV600E-mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard (https://clinical-trials.dimensions.ai/pharos/). CONCLUSION: For patients with treatment-naïve and previously treated BRAFV600E-mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.

Final Overall Survival, Safety, and Quality of Life Results From a Phase 2 Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced NSCLC.

Introduction: Crizotinib provided meaningful clinical benefit in the initial analysis of a phase 2 study in East Asian patients with advanced ROS1-positive NSCLC (NCT01945021). Nevertheless, overall survival (OS) data were immature. Here, we present the final OS, quality of life (QoL), and safety data after an additional 3 years of follow-up. Methods: In this phase 2, open-label, single-arm trial, East Asian patients with ROS1-positive advanced NSCLC who had received less than or equal to three systemic therapies previously were treated with crizotinib 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles. The OS (secondary end point) was analyzed for the total population, by country, and by number of previous chemotherapy regimens. QoL and safety were also evaluated. Results: With a median duration of follow-up of 56.1 months, the median OS was 44.2 months (95% confidence interval: 32.0-not reached) for the total population (N = 127). Differences in median OS were observed among individual countries and with number of previous regimens. The improvement in QoL found in the previous analysis was maintained with the extended follow-up. Treatment-related adverse events led to crizotinib dose reductions or permanent treatment discontinuations in 17.3% and 2.4%, respectively, of the patients. Conclusions: This is the largest trial of an ALK/ROS1 inhibitor to treat patients with ROS1-positive advanced NSCLC and provides a new benchmark for OS in East Asian patients. The QoL and safety profile with long-term follow-up were consistent with previous reports and support the continued use of crizotinib in the treatment of patients with ROS1-positive advanced NSCLC.

A phase 1b/2 study of PF-06747775 as monotherapy or in combination with Palbociclib in patients with epidermal growth factor receptor mutant advanced non-small cell lung cancer.

INTRODUCTION: This Phase 1/2 study (NCT02349633) explored the safety and antitumor activity of PF-06747775 (oral, third-generation epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer after progression on an EGFR inhibitor. METHODS: Phase 1 was a dose-escalation study of PF-06747775 monotherapy (starting dose: 25 mg once daily [QD]). Phase 1b/2 evaluated PF-06747775 monotherapy at recommended Phase 2 dose (RP2D; Cohort 1); PF-06747775 200 mg QD plus palbociclib (starting dose: 100 mg QD orally; Cohort 2A); and PF-06747775 monotherapy at RP2D in a Japanese lead-in cohort. RESULTS: Sixty-five patients were treated. Median treatment duration was 40.1 weeks. Monotherapy maximum tolerated dose was not determined. Two patients in Cohort 2A had dose-limiting toxicities. The monotherapy RP2D was estimated to be 200 mg QD. Most frequently reported adverse events (AEs) were diarrhea (69.2%), paronychia (69.2%), and rash (60.0%). Most AEs were grades 1-3. Overall, objective response rate (90% confidence interval [CI]) was 41.5% (31.2-52.5%). Median (range) duration of response was 11.09 (2.70-34.57) months. Median progression-free survival (90% CI) was 8.1 (5.4-23.3) months. CONCLUSIONS: PF-06747775 had a manageable safety profile and the study design highlights important considerations for future anti-EGFR agent development.

Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001.

BACKGROUND: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. METHODS: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. RESULTS: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. CONCLUSIONS: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. CLINICALTRIAL: gov: NCT00585195.

Effectiveness of crizotinib versus entrectinib in ROS1-positive non-small-cell lung cancer using clinical and real-world data.

Aims: To compare clinical trial results for crizotinib and entrectinib in ROS1-positive non-small-cell lung cancer and compare clinical trial data and real-world outcomes for crizotinib. Patients & methods: We analyzed four phase I-II studies using a simulated treatment comparison (STC). A STC of clinical trial versus real-world evidence compared crizotinib clinical data to real-world outcomes. Results: Adjusted STC found nonsignificant trends favoring crizotinib over entrectinib: objective response rate, risk ratio = 1.04 (95% CI: 0.85-1.28); median duration of response, mean difference = 16.11 months (95% CI: -1.57- 33.69); median progression-free survival, mean difference = 3.99 months (95% CI: -6.27-14.25); 12-month overall survival, risk ratio = 1.01 (95% CI: 0.90-1.12). Nonsignificant differences were observed between the trial end point values and the real-world evidence for crizotinib. Conclusions: Crizotinib and entrectinib have comparable efficacy in ROS1-positive non-small-cell lung cancer.

Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men.

This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n = 37, 8.5 months, 95% confidence interval (CI), 4.4-13.0) than ET alone (n = 214, 4.3 months, 95% CI, 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n = 26, 9.4 months, 95% CI, 4.4-14.0) than letrozole alone (n = 63, 3.0 months, 95% CI, 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.

Encorafenib plus binimetinib in patients with BRAFV600-mutant non-small cell lung cancer: phase II PHAROS study design.

BRAFV600 oncogenic driver mutations occur in 1-2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600-mutant NSCLC, as first- or second-line treatment. The primary end point is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy end points and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600-mutant NSCLC.

Plain language summary Some people with non-small-cell lung cancer (NSCLC) have changes in a gene called BRAF (known as 'gene mutations'). One common BRAF mutation is called 'V600'. Combinations of medicines that block proteins encoded by mutant BRAF and another gene called MEK can shrink tumors and slow their progression. We describe the design of PHAROS, a clinical trial investigating encorafenib (mutant BRAF inhibitor) combined with binimetinib (MEK inhibitor) in people with BRAF^V600-mutant NSCLC that had spread to other parts of the body ('metastatic disease'). People are monitored for side effects and to see if their tumor shrunk. PHAROS includes people treated with encorafenib plus binimetinib as their first treatment for metastatic disease, and people whose cancer progressed after previous anticancer therapy. Clinical trial registration: Clinicaltrials.gov (NCT03915951) and EudraCT (2019-000417-37).

Real-World Outcomes Among Crizotinib-Treated Patients with ROS1-Positive Advanced Non-Small-Cell Lung Cancer: A Community Oncology-Based Observational Study.

BACKGROUND: Crizotinib was the first oral targeted therapy approved by the US Food and Drug Administration (FDA), on 11 March 2016, for c-ros oncogene 1 (ROS1)-positive advanced non-small-cell lung cancer (NSCLC). Data to support long-term clinical benefit in a real-world setting are limited. OBJECTIVE: This study aimed to assess real-world clinical outcomes among patients with ROS1-positive advanced NSCLC treated with crizotinib in the US community oncology setting. PATIENTS AND METHODS: We conducted a retrospective cohort study using iKnowMed electronic health record data to identify adult patients with ROS1-positive advanced NSCLC who initiated crizotinib between 17 January 2013 (time of the addition of crizotinib for ROS1-positive NSCLC to National Comprehensive Cancer Network (NCCN) treatment guidelines) and 1 June 2019 with a potential follow-up period through 1 December 2019. Patient characteristics were assessed descriptively. Kaplan-Meier analyses were used to evaluate time to treatment discontinuation (TTD), time to next treatment (TTNT), and overall survival (OS). A Cox proportional hazards model was conducted to determine factors associated with OS. RESULTS: The study cohort included 38 ROS1-positive patients treated with crizotinib. The median age was 68 years (interquartile range 60.0-73.0) and 65.8% were female. Over 50% were current/former smokers, and 18.4% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Overall, 21 (55.3%) patients remained on crizotinib, 10 (26.3%) had evidence of subsequent treatment, and 16 (42.1%) died. The median TTD, TTNT, and OS were 25.2 months [95% confidence interval (CI): 5.2-not reached (NR)], 25.0 months (95% CI 5.2-61.0), and 36.2 months (95% CI 15.9-NR), respectively. In a multivariate Cox regression model, ECOG performance status of 2 was associated with a 4.9-fold higher risk of death (hazard ratio = 4.9; 95% CI 1.1-21.4) compared to ECOG performance status of 0 or 1. CONCLUSIONS: This ROS1-positive NSCLC real-world population was older and had a higher proportion of smokers and of patients with poorer ECOG performance status than those investigated in clinical trials. Nevertheless, our findings support the clinical benefit of crizotinib in this patient population with ROS1-positive advanced NSCLC.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.

Evaluation of the Effect of Proton Pump Inhibitors on the Efficacy of Dacomitinib and Gefitinib in Patients with Advanced Non-Small Cell Lung Cancer and EGFR-Activating Mutations.

INTRODUCTION: Dacomitinib and gefitinib are irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) indicated for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Pharmacokinetic (PK) studies in healthy volunteers suggested that acid-reducing drugs such as proton pump inhibitors (PPI) decreased dacomitinib and gefitinib exposure by limiting the pH-dependent absorption. This analysis retrospectively evaluates the effect of concomitant PPI use on dacomitinib exposure and on progression-free survival (PFS) and overall survival (OS) in patients treated with dacomitinib 45 mg QD or gefitinib 250 mg QD in a 1:1 randomized phase 3 study (ARCHER 1050). METHODS: The analysis grouped all patients (n = 452) treated in each arm of the study as non-PPI users, PPI users, or extensive PPI users. PFS and OS data were presented by Kaplan-Meier plots and analyzed using Cox proportional hazards models. Dacomitinib exposure was compared using a linear mixed-effects model. RESULTS: Results showed that dacomitinib PFS and OS did not differ significantly when comparing PPI users (N = 59) to non-PPI users (N = 152), while extensive PPI users (N = 24) had shorter PFS [hazard ratio (HR): 1.94, p = 0.011] and OS (HR: 1.77, p = 0.027) when compared to non-PPI users. For patients treated with gefitinib, PFS did not differ significantly when comparing PPI users (N = 51) and extensive PPI users (N = 19) to non-PPI users (N = 159); however, both PPI users (HR: 1.65, p = 0.007) and extensive PPI users (HR: 1.70, p = 0.050) had shorter OS when compared to non-PPI users. Further analysis by adjusting potential confounders indicated no statistically significant differences in PFS or OS between any PPI user vs. non-PPI user groups in the dacomitinib and gefitinib arms. PPI use did not appear to affect dacomitinib exposure. CONCLUSION: In conclusion, PPI use in patients with NSCLC likely has minimal impact on dacomitinib or gefitinib efficacy despite decreased absorption of these drugs observed in PK studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01774721.

Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050).

OBJECTIVES: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. MATERIALS AND METHODS: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. RESULTS: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively. CONCLUSION: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.

Crizotinib in Patients With MET-Amplified NSCLC.

INTRODUCTION: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC. METHODS: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival. RESULTS: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations. CONCLUSIONS: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. PATIENTS AND METHODS: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. RESULTS: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%-34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. CONCLUSIONS: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.See related commentary by Schulte and Eggert, p. 3507.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Performance Status Work Group.

PURPOSE: Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias. EXPERIMENTAL DESIGN: A multidisciplinary working group of the American Society of Clinical Oncology and Friends of Cancer Research evaluated how PS eligibility criteria could be more inclusive. The working group recommendations are based on a literature search, review of trials, simulation study, and multistakeholder consensus. The working group prioritized inclusiveness and access to investigational therapies, while balancing patient safety and study integrity. RESULTS: Broadening PS eligibility criteria may increase the number of potentially eligible patients for a given clinical trial, thus shortening accrual time. It may also result in greater participant diversity, potentially reduce trial participant and patient disparities, and enable clinicians to more readily translate trial results to patients with low-functioning PS. Potential impact on outcomes was explored through a simulation trial demonstrating that when the number of Eastern Cooperative Oncology Group PS2 participants was relatively small, the effect on the estimated HR and power was modest, even when PS2 patients did not derive a treatment benefit. CONCLUSIONS: Expanding PS eligibility criteria to be more inclusive may be justified in many cases and could result in faster accrual rates and more representative trial populations.See related commentary by Giantonio, p. 2369.

Outcomes in patients with lung cancer treated with crizotinib and erlotinib in routine clinical practice: A post-authorization safety cohort study conducted in Europe and in the United States.

PURPOSE: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice. METHODS: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately. RESULTS: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US. CONCLUSIONS: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases.

Indirect analysis of first-line therapy for advanced non-small-cell lung cancer with activating mutations in a Japanese population.

Background: Five EGFR-tyrosine kinase inhibitors (EGFR TKIs) are currently available in the first-line setting for non-small-cell lung cancer (NSCLC) in Japan. The aim here was to compare the relative efficacy of EGFR TKIs in the Japanese population. Materials & methods: A systematic review identified randomized controlled trials examining the efficacy of first-line EGFR TKIs. A Bayesian network meta-analysis was used to assess these EGFR TKI comparisons for progression-free survival (PFS). Results: A total of seven randomized controlled trials were identified and considered for network meta-analysis. Dacomitinib showed a trend toward improved PFS versus all comparators. Conclusion: Dacomitinib demonstrated a trend toward improved PFS and therefore, should be considered one of the standard first-line therapies for Japanese patients diagnosed with EGFR+ non-small-cell lung cancer.

Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations.

BACKGROUND: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. OBJECTIVE: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. PATIENTS AND METHODS: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). RESULTS: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. CONCLUSIONS: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212).

PURPOSE: This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL. METHODS: Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m2/dose BID. In Part A, patients received crizotinib oral solution (OS) in combination with topotecan and cyclophosphamide (topo/cyclo); in Part B, crizotinib OS was administered with vincristine and doxorubicin (vcr/dox). In Parts C and D, patients received topo/cyclo in combination with either crizotinib-formulated capsules (FC) or microspheres (cMS), respectively. Crizotinib pharmacokinetic evaluation was required. RESULTS: Forty-four eligible patients were enrolled, 39 were evaluable for toxicity. Parts A and B were terminated due to concerns regarding palatability and tolerability of the OS. In Part C, crizotinib, FC 215 mg/m2/dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m2/dose of crizotinib cMS. Pharmacokinetics of crizotinib in combination with chemotherapy was similar to single-agent crizotinib and exposures were not formulation dependent. CONCLUSIONS: The RP2D of crizotinib FCs in combination with cyclophosphamide and topotecan was 215 mg/m2/dose BID. The oral solution of crizotinib was not palatable in this patient population. Crizotinib cMS was palatable; however, patients experienced increased toxicity that was not explained by the relative bioavailability or exposure and warrants further investigation. CLINICAL TRIAL REGISTRY: The trial is registered as NCT01606878 at Clinicaltrials.gov.

Network meta analysis of first-line therapy for advanced EGFR mutation positive non-small-cell lung cancer: updated overall survival.

Aim: To update overall survival (OS) results from a previous network meta analysis comparing the relative clinical efficacy of epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR TKIs) for EGFR mutation positive (EGFR+) advanced non-small-cell lung cancer (NSCLC). Materials & methods: A Bayesian network meta analysis was conducted using updated/mature randomized controlled trial OS results in response to first-line EGFR TKI therapies. Results: Dacomitinib showed a numerical improvement of OS relative to other EGFR TKIs: afatinib (hazard ratio [HR]: 0.87; 95% credible interval [CrI]: 0.61-1.24), erlotinib (HR: 0.79; 95% CrI: 0.44-1.42), gefitinib (HR: 0.75; 95% CrI: 0.59-0.95) and osimertinib (HR: 0.94; 95% CrI: 0.68-1.29). Conclusion: Dacomitinib should be considered as a first-line treatment option for patients diagnosed with advanced EGFR+ NSCLC.