BACKGROUND-Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.

BACKGROUNDAlectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODSIn a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigatorassessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTSDuring a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P = 0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONSAs compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840.

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identifi ed as a potent, selective, and covalent KRAS G12C inhibitor that exhibits favorable drug-like properties, selectively modifi es mutant cysteine 12 in GDPbound KRAS G12C , and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRAS G12C -positive cell line-and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRAS G12C -positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profi ling in sensitive and partially resistant nonclinical models identifi ed mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE :The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRAS G12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identifi cation of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.

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 th...

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Summary Background Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib. Methods This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints. Findings A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4). Interpretation Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

Purpose Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients and Methods Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). Results At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Conclusion Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.

Purpose Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non–small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers. Experimental Design We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. Results Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5′ green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing. Conclusions Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.