Other molecular cohorts including ROS1, BRAF, HER2, MET, NTRK, RET, KRAS

Introduction

The treatment of non–small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy, whereby drugs would nonselectively kill both malignant tumor cells in addition to normal dividing or growing cells in the body. This resulted in undesirable adverse effects to normal organs. The “one-size-fits-all” approach to treatment has now evolved into more personalized treatment strategies dependent on histological subtypes and molecular mutations.

As the molecular mechanisms of carcinogenesis were discovered in the late 20th century, targeted therapy against the molecular pathways responsible for tumorigenesis became of increasing interest. By the early 2000s, therapeutic agents were being developed for this purpose with the hope that more selective therapy against tumor cells would spare normal cells to prevent undesired side effects. The most widely studied mutations in NSCLC consist of rearrangements in the anaplastic lymphoma kinase (ALK) gene or the epidermal growth factor receptor (EGFR) . These two mutations and their corresponding targeted therapies are specifically addressed in Chapters 10 and 11 . Since then, several other targetable oncogenic drivers have been identified ( Fig. 12.1 ). Studies show that patients with molecular mutations that can be treated with targeted therapy have a better prognosis than those without targetable mutations. The discovery of new molecular mutations has caused a paradigm shift toward the search for molecularly targeted agents against other driver mutations in NSCLC. Currently, several molecularly targeted tyrosine kinase inhibitors (TKIs) are available to treat patients with these molecular mutations and multiple agents are being studied in early- and late-phase clinical trials ( Fig. 12.2 ).

ROS-1

ROS-1 is a receptor tyrosine kinase encoded by c-ros on chromosome 6. The ligand for ROS-1 and the role of wild-type ROS-1 in humans remains unknown. Multiple ROS-1 fusion partners that have been identified in NSCLC cause constitutive tyrosine kinase activation resulting in downstream signaling to increase cell growth and proliferation and decrease apoptosis. ^, The CD74-ROS-1 fusion has been reported as the most common fusion in NSCLC. ROS-1 is closely related and structurally similar to the ALK oncogene. ^, The homology to ALK has been helpful in the development of ROS-1−directed therapies as many ALK inhibitors also inhibit ROS-1. In NSCLC, ROS-1 fusions occur in approximately 1%–2% of patients and are seen in a similar patient population to those with ALK gene rearrangements including younger age, never-smokers, and adenocarcinoma histology. ^, ROS-1 can be detected with fluorescence in situ hybridization (FISH) and immunohistochemistry; however, next-generation sequencing (NGS) is preferred as it can detect novel fusion partners.

Crizotinib and entrectinib are the only two US Food and Drug Administration (FDA)-approved treatments for patients with ROS-1 mutated NSCLC. The approval of crizotinib was based on the phase I PROFILE 1001 study, which showed an overall response rate (ORR) of 72%, median progression-free survival (PFS) of 19.3 months, and median overall survival (OS) of 51.4 months. Adverse effects were similar to the known side effect profile of crizotinib with vision disturbances, gastrointestinal side effects, edema, and elevated transaminases being the most common. Of note, subsequent studies have shown shorter PFS compared with that seen in the PROFILE 1001 study, ranging from 9 to 13 months. Lack of central nervous system (CNS) penetration is a known barrier of treatment with crizotinib, but newer ROS-1 TKIs including ceritinib, entrectinib, and lorlatinib have shown activity in the CNS.

Entrectinib is a ROS-1 and NTRK inhibitor with FDA approval was based on a pooled analysis of three clinical trials including patients with ROS-1 mutated NSCLC. Of 168 patients treated with entrectinib, the ORR was 68%, and the median PFS and median OS were 15.7 months and 47.8 months, respectively. Patients with baseline CNS disease had an ORR of 80% ( n = 24). Dysgeusia, gastrointestinal side effects, and dizziness were the most common side effects seen. Ceritinib is FDA approved for the treatment of patients with ALK-mutated NSCLC and has also shown activity in patients who have ROS-1 mutated disease. In a phase II study of 32 patients with ROS-1 mutated NSCLC, ceritinib showed an ORR of 62%, median PFS of 9.3 months, and median OS of 24 months. Adverse events were similar to the known side effect profile of ceritinib. Lorlatinib is a third-generation ALK and ROS-1 inhibitor that was studied in 69 patients with previously treated and treatment-naïve ROS-1 mutated NSCLC. The phase II trial showed an ORR of 62% in treatment-naïve patients and an ORR of 35% in patients previously treated with crizotinib. Intracranial responses were seen in both treatment-naïve patients and those with previously treated with crizotinib, happening in 64% and 50% of patients, respectively. Lorlatinib has a unique side effect profile compared with other ALK and ROS-1 inhibitors with CNS effects, fatigue, and hypercholesteremia being some of the most common adverse events. Management strategies for hypercholesteremia are discussed in Chapter 11 . Further strategies are needed to identify optimal sequencing of ROS-1 inhibitors and overcome resistance.

BRAF

The proto-oncogene B-Rapidly Accelerated Fibrosarcoma (BRAF) is a serine/threonine protein kinase that resides immediately downstream from KRAS and directly upstream from mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (MEK) in the MAPK pathway. The MAPK pathway mediates cell responses to growth signals for appropriate gene expression, cellular growth, and survival. When BRAF is mutated, MAPK is upregulated, causing cellular resistance to apoptosis and uncontrolled growth. A number of somatic point mutations of BRAF have been described, of which only the mutation amino acid position 600 (V600E) has FDA-approved targeted therapies at the present time. This has been more extensively applied in melanoma, where the majority of patients possess B-RAF ^V600E mutations. In NSCLC, 4% of patients harbor BRAF mutations and approximately 1%–2% of patients harbor a B-RAF ^V600E mutation specifically. Patients possessing the biomarker tend to be current or former smokers with adenocarcinoma or large cell carcinoma histological subtypes. Real-time polymerase chain reaction (PCR), Sanger sequencing, and NGS are the most sensitive and preferred methodologies for identifying BRAF mutational status.

Due to prior success in the treatment of B-RAF ^V600E -mutant melanoma, three BRAF-selective TKI regimens, vemurafenib, dabrafenib, and dabrafenib plus trametinib, have been investigated in patients with NSCLC who have progressed on chemotherapy with or without immunotherapy. Initially, phase II trials of vemurafenib and dabrafenib showed ORR in 42% and 33% of patients with a median PFS of 7.3 and 5.5 months, respectively ( Fig. 12.3 ). ^,

To delay tumor resistance to BRAF inhibition, concurrent downstream inhibition of MEK was proposed. It was already described in the melanoma literature that patients who received B-RAF ^V600E inhibition plus MEK inhibition had superior overall response, PFS, and OS compared with patients receiving BRAF-inhibitor monotherapy. This was the primary basis for a second cohort of patients in Planchard and colleagues’ phase II multicenter, nonrandomized, open-label study of dabrafenib who additionally received concurrent MEK inhibition therapy with trametinib. ^, Patients with stage IV B-RAF ^V600E -mutant NSCLC documented progression on platinum-based chemotherapy and three or fewer prior systemic treatments were eligible to enroll. Among the 57 pretreated patients included in the final analysis, 68.4% exhibited an overall response with a median PFS of 9.7 months and a duration of response of 10.2 months. Planchard and colleagues ^, also examined another cohort of 36 treatment-naïve patients with metastatic B-RAF ^V600E -mutant NSCLC patients who received the same dose of dabrafenib and trametinib. This smaller cohort had a similar ORR of 64% and a median PFS of 10.9 months. While toxicities of the combination regimen were higher relative to BRAF-inhibitor monotherapy, the two cohorts of combination regimen therapy had similar adverse effect profiles with dose reduction and dose interruption being more common with dabrafenib than trametinib (48% vs. 32% and 77% vs. 71%, respectively). The most common grade 3/4 adverse effects were pyrexia, vomiting, hypertension, hyponatremia, alanine aminotransferase and/or aspartate aminotransferase increase, ejection fraction decrease, anemia, and neutropenia. ^,

As a result of these trial data, in June 2017 the US Department of Agriculture approved the combination of dabrafenib plus trametinib for the treatment of metastatic B-RAF ^V600E −mutant NSCLC. The combination of B-RAF ^V600E plus MEK inhibition maintains longer PFS and more durable responses with improved tolerability and toxicity profiles compared with cytotoxic chemotherapy. Management of pyrexia that occurs with treatment of dabrafenib and trametinib is crucial because this is the main reason for treatment discontinuation in patients. Management strategies include testament interruptions and antipyretics. For patients with recurrent pyrexia, corticosteroids can be used. Therefore in patients with stage IV B-RAF ^V600E −mutant NSCLC, dabrafenib plus trametinib is the preferred first-line treatment versus systemic chemotherapy plus or minus immunotherapy based on the individual patient’s needs.