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Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL., Objective: This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel., Patients and Methods: The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/m 2 ) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m 2 , respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed., Results: Ten dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/m 2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m 2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively., Conclusions: The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m 2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors., Clinical Trials Registration: ClinicalTrials.gov NCT00975767; 11 September 2009., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Human epidermal growth factor receptor 2 (ERBB2) mutation is a known oncogenic driver mutation in a small proportion of non-small cell lung cancers (NSCLCs). Many targeted therapies are being developed and investigated for the treatment of ERBB2-mutated NSCLC, however none of these agents have yet been approved as a front-line treatment. Thus, platinum-based chemotherapy with or without immunotherapy remains the preferred first-line therapy for ERBB2-mutated NSCLC., Objective: We aimed to study the activity of chemotherapy in combination with pembrolizumab as first-line treatment in patients with stage IV ERBB2-mutated NSCLC., Patients and Methods: We retrospectively identified five patients with ERBB2-mutated NSCLC treated with carboplatin, pemetrexed and pembrolizumab as first-line therapy between 2018 and 2020. Overall survival (OS), progression-free survival (PFS), and time to next therapy (TTNT) were summarized by Kaplan-Meier methodology using R 4.0.5 with median time to event. Response rates defined by partial response (PR) or PR + stable disease (SD) and 95% Clopper-Pearson confidence interval (CI) were calculated., Results: The median age of these five patients was 60 years and all five patients' tumors had ERBB2 mutations-4 had exon 20 mutation and 1 had exon 23 mutation. With a median follow-up of 32 months, the median OS was 24 months, the median PFS was 9 months, and the median TTNT was 9 months. The response rate was 0.6 for PR (Clopper-Pearson exact 95% CI 0.147-0.947) and 0.8 for PR and SD (Clopper-Pearson exact 95% CI 0.284-0.995). No unexpected toxicities were observed., Conclusion: In a small number of patients, chemotherapy and pembrolizumab as first-line therapy in ERBB2-mutated NSCLC patients demonstrated activity similar to previous reports with this regimen. Future clinical trials are needed to determine the role of chemotherapy and immunotherapy for this patient population in the context of emerging targeted agents., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3-7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.