Biomarker Discovery Leads to Several Targeted Treatments in NSCLC

Wallace L. Akerley, MD

Clinical bias should not play a role in identifying patients with advanced non—small cell lung cancer (NSCLC) who may harbor rare molecular alterations. Rather, patients should undergo broad molecular profiling to determine whether they stand to benefit from the increasing array of highly specific targeted therapies that are showing tremendous responses, said Wallace L. Akerley, MD.

“[The management of patients with biomarkers] is kind of a holy grail; it's something we've been looking for, for a long time,” said Akerley, professor of internal medicine and director of the Lung Cancer Disease Center of Excellence at Huntsman Cancer Institute, University of Utah. “Traditionally, patients have been treated by whatever the textbook says. Now, we have biomarkers to tell us how patients should be treated. It's completely changed [how we treat patients with lung cancer].”

Among these biomarkers, MET exon 14 skipping mutations have shown a particular amenability to capmatinib, a highly selective MET inhibitor. According to data from the phase II GEOMETRY mono-1 trial, capmatinib elicited a 67.9% objective response rate (ORR; 95% CI, 47.6%-84.1%) per independent review in patients with previously untreated MET exon14-altered NSCLC.¹ Based on primary findings from this study, in September 2019, the FDA granted a breakthrough therapy designation to the MET inhibitor as frontline therapy in this indication, supplementing its existing designation following platinum-based chemotherapy.

Similarly, the FDA granted a breakthrough therapy designation in September 2019 to another investigational MET inhibitor, tepotinib, as a treatment for patients with metastatic NSCLC with  MET  exon14-skipping alterations who progressed on prior platinum-based chemotherapy.

In RET fusion—positive NSCLC, selpercatinib (LOXO-292) has also shown a significant response rate of 85% in the frontline setting, according to data from the phase I/II LIBRETTO-001 trial with a median progression-free survival approaching 2 years.² As such, a new drug application for the RET inhibitor is expected to be submitted to the FDA within the year.

Although HER2 mutations are rare in NSCLC, they should also be accounted for, according to Akerley, as there are several HER2-targeted therapies currently under evaluation.

In an interview during the 2019  OncLive  State of the Science Summit on Non—Small Cell Lung Cancer, Akerley, who is also a member of the National Comprehensive Cancer Network (NCCN)’s Steering Committee for Small Cell Lung Cancer Panel and NSCLC Panel, University of Utah Health, discussed targeted approaches for patients with NSCLC who harbor alterations in MET, RET, and HER2, as well as the importance of broad molecular profiling.

OncLive: How is MET being used as a biomarker in lung cancer?

Akerley: There are several new biomarkers in lung cancer. MET is a very important marker at this point; it’s unique in the sense that it can be both a resistance marker as well as a primary driver of lung cancer. MET exon 14 skipping mutations are not that common but are common enough [to warrant a treatment to target them]. We have been a part of a phase II study examining capmatinib, results of which were presented at the 2019 World Conference on Lung Cancer. It's a remarkable drug; it [has shown a high response rate around 70%]. A large fraction of patients [on this agent] have stable disease. Disease control is a critical issue for patients, but almost everyone benefits in that regard. Several patients have been on treatment for about 1.5 years, and median survival times are exceeding 1.5 years. Moreover, [the agent] crosses the blood—brain barrier, it’s easy to take, and the tolerability is very good. These patients can be very sick, but treatment with [this] agent can improve their performance status.

What data exist with RET targeted therapy?

Of all of the kinase inhibitors that I have used in lung cancer, [selpercatinib] is the most exciting. The agent has a response rate in the 80% range, and a very large fraction of patients have stable disease. The drug is highly specific. With many of the drugs we have hit a lot of kinases, but this one is specific to the RET mutation. Moreover, we're able to give extremely high doses with almost no adverse events because there's very little off-target toxicity. The improvement in performance status has been remarkable. Patients have gone from being bedridden to being strong enough to return to work. The quality of the response, the blood—brain barrier penetration, and the duration of the response [seen with this agent] have been overwhelming. 

The drug is expected to be approved [by the FDA] in the very near future. The large phase I study is about to close, but there will be a large number of phase II studies that will open. The proof-of-principle has [been proven]. [I predict that] the drug will become commercially available for everyone in the near future. 

What are some of the agents that are showing activity against HER2?

The world of lung cancer has changed dramatically. Everyone is aware of EGFR, ALK, ROS1, and BRAF; those are the “gold standards,” but several rare mutations also show up and have activity. We've been using ado-trastuzumab emtansine (T-DM1; Kadcyla) [off-label] for patients with HER2 mutations, but there are several other oral agents that can be used in clinical trials. [This approach] does work, but only if you look for the HER2 mutation. [We can order] a single mutation test or polymerase chain reaction-based assay, which is great, but the NCCN and most lung cancer physicians would recommend a broad panel. If you don't look for opportunities for treatment, you're going to miss them. HER2 is not very common; it occurs in approximately 2% of [patients with lung cancer], but for those 2% of patients, you can get a very strong response with [HER2-targeted therapy].

Should every patient undergo broad molecular testing?

You have to give everyone the chance. It's simple to say most mutations show up in never-smokers, but there are patients who have smoked heavily and there are those who rarely smoked and quit 20 or 30 years ago. It's imperative that you do not miss any never-smokers.

It's important that everybody get a molecular panel and undergo immune testing. Presently, immune testing is limited to PD-L1 overexpression, but tumor mutational burden is a second marker that can be used to define populations that are more likely to benefit from immunotherapy beyond PD-L1 inhibitors. We're going to have a whole slew of these as time goes by. Investigators have recently been looking at STK11 and LKB1 as negative predictors of response.

References

1. Wolf J, Seto T, Han J-Y, 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(15 suppl; abstr 9004). doi: 10.1200/JCO.2019.37.15_suppl.9004.
2. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.08.