Selective Inhibitors of Rare Mutations Show Encouraging Activity in NSCLC

Jessica J Lin, MD

Selective inhibitors for patients with non—small cell lung cancer (NSCLC) with rare oncogenic drivers, such as RET fusions, KRAS^G12C mutations, and MET exon 14 alterations, are showing high response rates in clinical trials, explained Jessica Jiyeong Lin, MD.

Most recently, preliminary efficacy data with the RET inhibitor BLU-667 presented at the 2019 ASCO Annual Meeting showed an objective response rate (ORR) of 58% and a disease control rate of 96% among previously treated patients with RET fusion—positive NSCLC.¹ A similar magnitude of benefit has also been reported with another RET inhibitor, LOXO-292. Now, both agents have been granted breakthrough therapy designations from the FDA.

Treatment with the KRAS^G12C inhibitor AMG 510 also led to a significant response rate of 50% in a small cohort of patients with advanced KRAS^G12C—positive NSCLC enrolled in a phase I study.²

In the MET space, updated analyses for capmatinib (INC280) and tepotinib induced deep and durable responses in treatment-naïve patients with MET exon 14—altered tumors and those previously exposed to 1 prior line of therapy. Specifically, capmatinib showed an objective response rate (ORR) by independent review (IR) of 67.9% in this patient population, according to data from the phase II GEOMETRY trial,³ and tepotinib showed a 58.8% ORR by IR among this patient population in the phase II VISION trial.⁴

“We really should be pursuing broad molecular profiling outside of testing for EGFR mutations, ALK and ROS1 rearrangements, and BRAF mutations, when patients are initially diagnosed with advanced NSCLC,” said Lin, an attending physician in the Center for Thoracic Cancers and Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital. “We now have several additional targets for which we have effective drugs that are available, even if it is in a clinical trial setting.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Lin, who is also an instructor at Harvard Medical School, discussed these targets and elaborated on the updated efficacy analyses that were presented at the 2019 ASCO Annual Meeting.

OncLive: Could you discuss some of the emerging biomarkers in NSCLC?

Lin: Until recently, we did not have effective targeted treatment options for our patients with advanced RET fusion—positive lung cancer. The only targeted treatment options that we had were multikinase inhibitors, which have several other targets in addition to RET. We saw quite a bit of toxicity in clinic with these multikinase inhibitors as well as suboptimal efficacy.

Now, we are quite excited because we have 2 very potent and selective RET inhibitors that are available in clinical trials: BLU-667 and LOXO-292. I discussed the efficacy that we have seen from early data. Justin Gainor, MD, of Massachusetts General Hospital, presented the updated preliminary efficacy in patients with BLU-667 in [patients with] advanced RET fusion—positive lung cancer at the 2019 ASCO Annual Meeting. The ORR was about 58% with the agent, which is quite good.

We heard about the preliminary efficacy of LOXO-292 in patients with RET fusion—positive lung cancer at the 2018 World Conference on Lung Cancer. [At that time, the ORR] was 68%. Both agents have shown promising activity, and both agents have been generally well tolerated. Moreover, both drugs have received FDA breakthrough therapy designations for use in previously treated patients with advanced RET fusion—positive lung cancer.

That is a great example of how the field is actively moving forward. We have better drugs that are available that are easier for patients to take. We are looking forward to seeing more data regarding [agents in development for] this subset of lung cancer.

Do the data presented at the 2019 ASCO Annual Meeting regarding BLU-667 warrant an accelerated approval?

There is a very strong rationale [for an approval] in terms of the preliminary efficacy we have seen [with BLU-667] as well as its tolerability profile. This is certainly in an area where there is an urgent need for better treatment options for our patients, so yes.

Could you shed light on other emerging biomarkers?

KRAS^G12C inhibitors are certainly some of the most exciting drugs [for which] we have been looking forward to [seeing more data]. One of the key presentations at the 2019 ASCO Annual Meeting [focused on one of those agents]. KRAS mutations comprise approximately 30% of all NSCLCs and despite this, KRAS has been incredibly difficult to target. We still do not have effective targeted therapy options available for patients with KRAS-mutant lung cancer.

For the first time, we saw early data for a covalent irreversible inhibitor of the KRAS^G12C—mutant kinase: AMG 510. Ten patients with KRAS^G12C-mutant lung cancer were evaluated; of those patients, 5 had partial responses, which is quite promising. We were all excited to see that, and the toxicity profile was also quite favorable. That was a very good presentation. We really need to see how the numbers look with further follow-up and with a larger panel of patients, but those data speak well for Amgen 510, as well as the additional KRAS^G12C inhibitors that are currently in development.

We also saw very exciting data for 2 MET inhibitors for patients with MET exon 14—altered lung cancer. Updated data for both capmatinib and tepotinib were presented at the 2019 ASCO Annual Meeting, and both agents are showing very good activity in patients with MET exon 14—altered tumors. In the first-line setting, capmatinib showed a response rate of over 60%, which is better than what we have seen so far with other MET inhibitors. Both capmatinib and tepotinib showed great activity, including in previously treated patients with MET exon 14—altered lung cancer.

Could you speak to the potential of TAK-788 and poziotinib?

TAK-788 and poziotinib are inhibitors of EGFR exon 20 insertion mutations as well as HER2 exon 20 mutations. Both HER2 exon 20— and EGFR exon 20—altered tumors have traditionally been lacking in terms of effective targeted treatment options. With both agents, we are seeing promising activity in patients with both EGFR- and HER2-altered lung cancers. It is too early to compare the agents across trials. We really have to see how the response rates, the progression-free survival, and the tolerability profiles compare as more patients enroll. However, both drugs are promising at this time.

References

1. Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15, abstr 9008). doi: 10.1200/JCO.2019.37.15_suppl.9008.
2. Fakih M, Price TJ, O’Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J Clin Oncol. 2019;37(suppl 15, abstr 3003). doi: 10.1200/JCO.2019.37.15_suppl.3003.
3. Wolf J, Seto T, Han J-H, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019;37(suppl 15, abstr 9004). doi: 10.1200/JCO.2019.37.15_suppl.9004.
4. Pail PK, Vellion R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol. 2019;37(suppl 15, abstr 9005). doi: 10.1200/JCO.2019.37.15_suppl.9005.