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This article reviews the role of ALK tyrosine kinase inhibitors (TKIs) in the literature and provides expert commentary on local use in Argentina, Brazil, China, Russia, South Korea, and Turkey. We identified 56 articles involving patients with ALK-positive non-small cell lung cancer (NSCLC) and brain metastases (BM) treated with ALK TKIs published between January 2000 and June 2021. In first-line settings, central nervous system response rates in clinical trials with alectinib (86-94%), brigatinib (67-78%), and lorlatinib (42-82%) were generally higher than those reported with crizotinib (16-71%). Median progression-free survival in patients receiving crizotinib (5.6-7.4 months) was lower than alectinib (not reached), brigatinib (24.0 months), and ceritinib (10.7-25.2 months). Across these counties, next-generation TKIs are preferred for patients with progressing BM lesions. Although next-generation ALK TKIs demonstrate significant activity in these patients and following progression on crizotinib, access remains a challenge for personalized therapy.

In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.Patients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.A similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43-0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49-0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.These data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.

TPS8606 Background: Current standard of care immunotherapy plus chemotherapy options for first-line extensive-stage small-cell lung cancer (ES-SCLC) are associated with modest improvements in median OS and PFS. In the KEYNOTE-604 study, first-line pembrolizumab plus etoposide/platinum (EP) significantly improved PFS (HR 0.75; 95% CI, 0.61‒0.91; P = 0.0023) compared with placebo plus EP in ES-SCLC; OS was also longer with pembrolizumab plus EP vs placebo plus EP but did not reach statistical significance (HR 0.80; 95% CI, 0.64‒0.98; P = 0.0164). Preclinical and clinical data suggest that blocking the interaction between the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and its ligands CD112 and CD155 with the anti-TIGIT humanized monoclonal antibody vibostolimab (MK-7684) yields promising antitumor activity when combined with pembrolizumab, with or without chemotherapy, including in patients with lung cancer. The current phase 3 study, KeyVibe-008 (NCT05224141), is comparing the efficacy and safety of first-line treatment with MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, in combination with EP vs atezolizumab plus EP in patients with ES-SCLC. Methods: This multicenter, randomized, double-blind, phase 3 study is enrolling patients aged ≥18 years with histologically or cytologically confirmed, previously untreated ES-SCLC. Patients must have measurable disease per RECIST v1.1; ECOG PS of 0 or 1; no active CNS metastases/carcinomatous meningitis, autoimmune disease, neurologic paraneoplastic syndromes, pneumonitis, or interstitial lung disease; and must provide a pretreatment tumor sample. Patients are randomized 1:1 to receive up to 4 cycles of EP (cisplatin or carboplatin) in combination with MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) Q3W or atezolizumab (1200 mg) Q3W, followed by MK-7684A or atezolizumab, respectively, until disease progression, unacceptable AEs, intercurrent illness, protocol violation, or investigator/patient decision. Randomization is stratified by ECOG PS (0 vs 1), LDH (≤ULN vs > ULN), liver metastases (yes vs no), and brain metastases (yes vs no). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review; safety; and patient-reported outcomes (PROs). Tumor imaging occurs at baseline, every 6 weeks until 48 weeks, and every 9 weeks thereafter until disease progression, start of new anticancer treatment, withdrawal of consent, or death. PROs are assessed using validated instruments including the EORTC quality of life and EuroQol questionnaires. AEs are graded according to NCI CTCAE v5.0. Enrollment is ongoing worldwide. Clinical trial information: NCT05224141.