New Targets in Lung Cancer Shape Treatment Options

H. Jack West, MD


July 16, 2019

In lung cancer, trials of new targets were among the most clinically relevant presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO). Several emerging targets had data so compelling that they now deserve to shape our treatment decisions, because there are agents available in trials or that may receive approval by the US Food and Drug Administration (FDA) by the time an oncologist identifies the next patient with that specific target.

MET Exon 14 Mutation-Positive NSCLC

MET exon 14 mutations, seen in about 3% of patients with lung cancer,[1] have been the subject of several previous studies, and this biomarker is currently listed in the National Comprehensive Cancer Network guidelines as a potential target for crizotinib.[2] At ASCO, we saw results with two other agents that exceeded prior benchmarks.

First, the MET inhibitor capmatinib was administered orally at 400 mg twice daily to both treatment-naive and previously treated patients with advanced non–small cell lung cancer (NSCLC) harboring a MET exon 14 mutation.[3] According to the blinded independent review committee (BIRC), previously treated patients (n = 69) demonstrated an objective response rate (ORR) of 41% and a disease-control rate (DCR) of 78%. Among treatment-naive patients (n = 28), the ORR was 68% and the DCR was 96%. Median progression-free survival, as assessed by the BIRC, was 4.8 and 11.1 months in previously treated and treatment-naive patients, respectively.

The oral MET tyrosine kinase inhibitor tepotinib was also studied, at 500 mg daily in patients with MET exon 14 mutation-positive advanced NSCLC.[4] This study reported an approximately 50% ORR across many groups, whether the MET exon 14 mutation was detected by tissue (n = 57) or plasma (n = 58), and without any clear difference in efficacy between treatment-naive and previously treated patients. The median progression-free survival as assessed by a BIRC was 9.5 months in the cohort with MET exon 14 mutations detected by tissue biopsy and 10.8 months in those detected with plasma.

Both of these agents shared a very similar side-effect profile, with peripheral edema followed by nausea as the leading issues, though rarely grade 3 or higher.

RET Fusions

RET fusions, seen in approximately 1%-2% of patients with advanced NSCLC,[5] are another biomarker now definitely worth identifying. The investigational agent LOXO-292 has already demonstrated remarkable activity in this narrow subgroup of patients,[6] and at ASCO 2019 we saw the results of a phase 1/2 trial of the potent and selective RET inhibitor BLU-667 at a starting dose of 400 mg daily, given orally.[7] This trial reported an ORR of 58% and a DCR of 96% among 48 patients overall, many with prolonged and ongoing responses. The trial also demonstrated that BLU-667 has good activity regardless of prior platinum chemotherapy or immunotherapy exposure and activity in patients with brain metastases, including intracranial responses. Constipation, neutropenia, liver function test abnormalities, fatigue, and hypertension were the most common side effects, but these were generally low-grade.

Referral—and FDA Approval—Warranted

Despite the relatively limited numbers of patients in these trials, the results are so consistent and impressive that they merit FDA approval and wide use for appropriate patients once available. Until that time, these agents confer such significant benefits that patients harboring a MET exon 14 mutation or RET fusion should be referred to receive an appropriate agent in the context of a clinical trial or expanded-access program. While it may be debatable whether these agents should be used as first-line therapies or deferred, they are too effective for appropriately selected patients to miss the opportunity to benefit.

Targeting KRAS

Along with these dramatic results in narrow populations, ASCO 2019 included a very early report that probably flew under the radar of many but could prove to be among the most important developments in targeted therapy in lung cancer. Our nemesis, KRAS, is the most common mutation in lung cancer, seen in 20%-25% of cases,[8] but trials testing potential treatments for KRAS mutation-positive NSCLC have failed for decades.[8]

AMG 510 is a novel small-molecule inhibitor targeting the KRAS G12C mutation, which comprises about 13% of advanced NSCLC.[9] The drug was studied in a multicenter phase 1 trial of escalating doses in heavily pretreated patients with KRAS G12C mutation-positive solid tumors (100% had received at least two prior lines of therapy).[9]

The results presented were preliminary and featured only a very limited number of patients, but they were notable: Five of 10 patients demonstrated a partial response (four confirmed) and all were still on treatment. Though mild gastrointestinal and a few other miscellaneous adverse events (AEs) were reported, there have been no dose-limiting, grade 4, or serious related AEs in enrolled patients. Clearly the early responses seen among the first 10 patients are not sufficient to declare this new therapy practice-changing, but these results offer a glimpse of a drug with impressive activity in previously treated patients with KRAS mutation-positive NSCLC, a population to whom we have had too little to offer for far too long.

We came away from ASCO 2019 with several additional targets in lung cancer that merit testing and prioritizing for targeted therapy when identified. MET exon 14 mutations and RET fusions have associated treatments with response rates that are as high as or exceed those of our leading nontargeted first-line therapies, and we should expect to have FDA-approved and commercially available options soon.

For the 13% of patients with a KRAS G12C mutation, AMG 510 offers what I would consider the most promising lead we've ever had for a strong, KRAS-targeted therapy, though we will need far more patients in trials to confirm that.

In the meantime, we have so many critical molecular targets in lung cancer that it is now appropriate to pursue broad next-generation sequencing panels in more patients. Our treatments are too effective to miss the opportunity to identify the best biomarker-driven therapy for them.

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