Associate Director, Drug Development
Sarah Cannon Research Institute
Tennessee Oncology, PLLC
Todd M. Bauer, MD, has disclosed that he has received funds for research support paid to his institution from AbbVie, Aileron, Amgen, Armo, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera, Clovis, Daiichi Sankyo, Deciphera, Five Prime, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Immunocore, Incyte, Immunogen, Jacobio, Janssen, Leap, Lilly, Loxo, Karyopharm, Kolltan, MabVax, MedImmune, Medpacto, Merck, Mirati, Merrimack, Moderna, Novartis, Onyx, Peleton, Pfizer, Phosplatin, Principa, Roche, Sanofi, Stemline, Takeda, and Top Alliance BioScience; has received consulting fees paid to his institution from Ignyta, Moderna, and Pfizer; has received consulting fees from Blueprint Medicine, Exelixis, Foundation Medicine, Loxo, and Pfizer; and has served on the speaker bureau for Bayer.
Lung cancer continues to be on the cutting edge of targeted therapies. The range of actionable targets has expanded from EGFR mutations to now encompass alterations in ALK, ROS1, BRAF, and more. In patients with lung cancer and known oncogenic drivers, we can substantially improve survival by leveraging targeted therapies, thereby making biomarker testing in these patients of critical importance. In this commentary, I preview 2 key biomarkers poised to enter the clinic in 2020, RET and MET exon 14 (METex14), and revisit 2 biomarkers already in practice, NTRK and ROS1.
Biomarkers Entering the Clinic in 2020: RET Fusions and METex14 Skipping Mutations
The first imminent biomarker poised to change lung cancer care in the near future is the RET gene. RET rearrangements with a fusion partner (eg, KIF5B) occur in up to 2% of advanced non-small-cell lung cancer (NSCLC). RET point mutations also occur in NSCLC but are rare. Two oral, selective RET inhibitors are in late-stage development for several indications, including advanced RET fusion–positive NSCLC: selpercatinib (LOXO-292) and pralsetinib (BLU-667). Both are associated with rapid and prolonged antitumor effects, typically with limited and low-grade adverse events (AEs).
Selpercatinib is under FDA priority review for several indications, including advanced RET fusion–positive NSCLC, based on positive results from the registrational phase I/II LIBRETTO-001 trial. At WCLC 2019, Drilon and colleagues reported that selpercatinib was associated with an ORR of 68% and a median duration of response of 20.3 months in patients with RET fusion–positive NSCLC previously treated with platinum-based chemotherapy. In those with previously untreated, RET fusion–positive NSCLC, the ORR was 85%. Most of the AEs were low grade, with the most common being dry mouth, diarrhea, hypertension, and increased ALT/AST. The PDUFA date for selpercatinib is scheduled for the third quarter of 2020.
Pralsetinib has been submitted to the FDA for RET fusion–positive NSCLC based on positive data from the phase I/II ARROW trial. In patients previously treated with platinum-based chemotherapy, the ORR was 60% and the median duration of response was not reached. In previously untreated patients, the ORR was 73%. The AEs observed with pralsetinib were low grade and reversible, with constipation, neutropenia, increased AST, and fatigue being the most common.
As we await approval of these agents, I would recommend that any patient with newly diagnosed NSCLC who tests positive for a RET fusion be enrolled on a RET inhibitor clinical trial, including on LIBRETTO-001 or ARROW, especially given the favorable safety profile of RET inhibitors as compared with chemotherapy. There are also phase III trials under development for these agents, including LIBRETTO-431 and AcceleRET comparing first-line selpercatinib and pralsetinib, respectively, to platinum-based chemotherapy with or without pembrolizumab for advanced or metastatic RET fusion–positive NSCLC.
METex14 Skipping Mutations
Another biomarker for NSCLC I foresee reaching the clinic in 2020 is the METex14 alteration, which occurs in up to 4% of NSCLC. Although inhibiting MET is not a brand new idea, recent promising clinical data with the oral, selective MET inhibitors capmatinib and tepotinib in METex14-positive NSCLC suggest that we could soon see FDA approvals for these new agents, both of which are well tolerated and can have a rapid, sustained effect on METex14-positive tumors.
Capmatinib is under FDA priority review for METex14-positive advanced/metastatic NSCLC, whether newly diagnosed or previously treated. In the phase II GEOMETRY mono-1 trial, capmatinib was associated with an ORR of 40.6% in previously treated patients and 67.9% in untreated patients, with durable responses lasting a median of 10 and 11 months, respectively. The intracranial ORR was 54%. The most common treatment-related AEs were peripheral edema, nausea, increased blood creatinine, and vomiting, which were predominantly grade 1/2.
In September 2019, tepotinib was granted a breakthrough therapy designation by the FDA for patients with METex14-positive metastatic NSCLC previously treated with platinum-based therapy. This designation was based on positive results from the phase II VISION trial in patients with METex14-positive NSCLC, including an ORR of 45.1% based on tissue biopsy and 50.0% based on liquid biopsy, with a median duration of response of more than 12 months. The most common treatment-related AEs were peripheral edema, nausea, and diarrhea, with most events being low grade.
Finally, the multikinase inhibitor crizotinib—which is approved by the FDA for treatment of ALK- and ROS1-rearranged NSCLC—was recently shown to induce durable responses in patients with previously treated METex14-positive NSCLC in a phase I trial, with an ORR of 32% and a median duration of response of 9.1 months.
Based on current data, I would consider enrollment on these clinical trials a good option for patients with METex14-positive NSCLC after failing an FDA-approved first-line therapy.
Revisiting Biomarkers Already in Practice: NTRK and ROS1
NTRK fusions that constitutively activate TRK receptors are rare in NSCLC (< 1%), but there are 2 FDA-approved kinase inhibitors in this setting that provide a life-altering opportunity for treatment in patients in whom this genomic aberration is found. Entrectinib (ROS1/TRK/ALK TKI; approved by the FDA for adults and pediatric patients 12 years of age or older) and larotrectinib (TRK-specific TKI; approved for adults and all pediatric patients) are both indicated for patients with solid tumors that have an NTRK fusion lacking a known acquired resistance mutation, whose disease is metastatic or cannot be surgically resected without severe morbidity, and who have progressed on or following standard therapy or lack satisfactory alternative treatments.
Tumor responses to these agents are impressive. In pooled analyses of early phase studies in TRK fusion–positive cancers, entrectinib achieved an ORR of 57.4% (7.4% with CR), with a 10.4-month duration of response, and larotrectinib achieved an ORR of 75% (13% with CR), with 71% of the responses ongoing and 55% of the patients remaining progression free at 1 year.
Testing for NTRK fusions can be challenging, especially because not all molecular profiling assays test for fusions in all 3 NTRK genes (NTRK1, NTRK2, and NTRK3). So I think this continues to be an area where physicians need to talk with their pathologist and talk with the molecular profiling vendors to ensure that they are getting all the information they think they are getting when they request a test for these fusions. Regardless, testing for NTRK fusions is worthwhile to find that one patient who has this alteration, and even if a fusion is not identified, by testing for this rare marker, we increase the opportunity of finding other actionable mutations.
Even for genomic aberrations that have been in the clinic for some time, new agents that improve outcomes for patients continue to be developed and approved for those targets. ROS1 rearrangements, which occur in up to 2% of patients with advanced NSCLC and are part of the standard testing paradigm in NSCLC, are one such example.
Until recently, the multikinase inhibitor crizotinib was the only TKI approved by the FDA for the treatment of newly diagnosed ROS1-positive NSCLC. That changed in August 2019 when the FDA approved entrectinib for ROS1-positive metastatic NSCLC, an approval that does not seem to have been fully appreciated due to a simultaneous wealth of progress in the treatment of NSCLC. This approval was based on the ALKA-372-001, STARTRK-1, and STARTRK-2 trials, which reported an ORR of 78% in adults with ROS1-positive NSCLC. Guidelines now recommend entrectinib and crizotinib as preferred regimens for first-line treatment of ROS1-positive NSCLC, so keeping abreast of not only new targets and their associated agents, but also of new drugs for older targets continues to be an important area of opportunity for physicians to remain current with treatment options for their patients.
Practical Recommendations for Testing
I would like to stress that all patients with metastatic lung cancer should undergo molecular profiling of their tumors to look for known mutations and, in some cases, currently uncharacterized mutations. Finding a mutation can help direct patients toward approved or investigational regimens that have the potential to improve outcomes. Even negative test results can still guide therapy selection by steering patients away from drugs or clinical trials that are not likely to help them. For those clinicians who think their odds of finding a low frequency mutation are not that great, I counter that, when we add up all of the known oncogenic drivers, approximately one half of patients with lung cancer will have an actionable target that can guide treatment selection, whether an FDA-approved therapy or on a clinical trial.
I also advise casting a wide net by using broad next-generation sequencing (NGS) testing rather than taking a sequential approach to testing individual biomarkers, especially considering the growing number of alterations in lung cancer for which clinicians need to test. Performing NGS once is generally quicker and more cost‑effective than sequentially performing individual tests at a local laboratory and is more likely to identify an actionable mutation.
Furthermore, even though tissue remains the gold standard for testing, emerging data suggest a high concordance between blood‑based assays and tissue‑based assays. Given that tumor tissue is often limited, using blood‑based biopsies to look for ctDNA can accelerate testing turnaround time and allow for more rapid initiation of effective targeted therapy, as well as avoiding risks associated with repeat biopsies (eg, pneumothorax). However, although we can make treatment decisions based on a positive liquid biopsy result, it is important to remember that a negative result could be a false negative and requires confirmation with testing of a tissue biopsy.
Finally, with so many biomarkers being assessed, when should we make decisions on treatment? I recommend waiting for the results from NGS or targeted biomarker testing before acting on PD-L1 results for immunotherapy. Data suggest that immunotherapy lacks efficacy in patients with PD-L1–positive, EGFR-mutated NSCLC. Furthermore, there is evidence that sequencing a TKI after immune checkpoint inhibitors may increase rates of severe immune-related AEs, in particular pneumonitis. However, the reverse therapeutic sequence of an immune checkpoint inhibitor regimen following a TKI does not appear to be associated with an increased risk of an immune-related AEs.Keep abreast of new developments in lung cancer biomarkers and associated targeted therapies by continuing to follow CCO and this educational program! Visit the program page to learn more about leveraging targeted agents in lung cancer care with downloadable slides and on-demand Webcasts from live meetings, a biomarker summary handout, and a treatment decision support tool (all forthcoming in 2020).
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