Pralsetinib and Selpercatinib Expand the RET+ NSCLC Paradigm

The recent FDA approvals of pralsetinib (Gavreto) and selpercatinib (Retevmo) have led to expanded treatment options for patients with non–small cell lung cancer (NSCLC) who harbor RET rearrangements, but Justin F. Gainor, MD, emphasized that these approvals stress the need for more robust molecular testing.

In May 2020, the FDA granted selpercatinib an accelerated approval for adults with RET fusion–positive NSCLC based on the overall response rate and response duration data from the phase 1/2 LIBRETTO-001 study.¹ Shortly thereafter, in September of 2020, the FDA granted another accelerated approval to pralsetinib for adults with metastatic RET fusion–positive NSCLC based on similarly positive efficacy data from the phase 1/2 ARROW trial.²

“This is really exciting. We now have 2 FDA-approved therapies for patients with RET fusion–positive lung cancer,” said Gainor. “Based upon the impressive data in the treatment-naïve setting, these agents should be considered a new standard of care for those patients.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Gainor, director of the Center for Thoracic Cancers and Targeted Immunotherapy at Massachusetts General Hospital, as well as an assistant professor of medicine at Harvard Medical School, discussed the importance of genetic testing in lung cancer, as well as several other molecular targets that are being examined.

OncLive®: What recent developments in molecular testing have had implications in clinical practice?

Gainor: Lung cancer has evolved dramatically over the last 15 years. That has really been driven by the recognition that lung cancer is actually a heterogeneous disease and is defined by different genetic alterations and nonpathogenic drivers. We now have 7 different molecular alterations with FDA-approved targets, as well as several other genetic alterations with promising targeted therapies. It has led to this very rich environment for targeted therapies and also underscores the absolute importance of doing comprehensive genetic profiling that identify newly diagnosed lung cancers in order to pursue precision medicine and give patients the best therapies.

For the most part, out of very rare instances of the genetic alterations that we're dealing with in lung cancer, these are somatic alterations; [sometimes] we are dealing with are germline alterations. Just this year, we now have 2 additional approved molecular targets. These are MET exon 14 skipping [mutations], as well as RET rearrangements. We now have FDA-approved therapies for both of those alterations, bringing up the number of targets to 7 with approved therapies. It just emphasizes that [with] broad-based testing, we can no longer just focus on a few alterations, such as EGFR and ALK. Now with 7 different alterations, you need to do multiplex testing—ideally with next-generation sequencing, because sequential testing strategies are not going to be sufficient to provide the best care.

Test, test, test. It's absolutely important to do broad multiplex genotyping. [Secondly, do] not start therapy until you have those genetic results available, if possible. Those are the 2 big points. Other than that, it is exciting that in lung cancer we continue to carve out distinct molecularly defined subsets with now highly active targeted therapies. This is really a model disease for improving patient outcomes by gaining a better understanding of the molecular underpinnings of the disease.

What did you find most intriguing from the LIBRETTO-001 results?

RET rearrangements are found in approximately 1% to 2% of patients with NSCLC. RET rearrangements are also found in several other solid tumors, the most notable other example is papillary thyroid cancer. These are bona fide oncogenic drivers. In lung cancer, we've known about these alterations since 2012, but the early drugs targeting RET fusions were really repurposed drugs. These were multikinase inhibitors that were approved for other indications and clinicians tried acting on the new discovery rearrangements and really repurpose these drugs.

Unfortunately, with those multikinase inhibitors the activity was fairly modest because they weren't very good RET inhibitors; they hit other [targets], as the name implies. Beginning around 2017, though, we saw 2 selective RET inhibitors enter clinical testing. These drugs selpercatinib and pralsetinib were designed to target RET.

The LIBRETTO-001 study [examined] selpercatinib in patients with RET fusion­–positive lung cancer, as well as with other RET-driven malignancies, such as medullary thyroid cancer and papillary thyroid cancer. What we saw was very impressive activity in RET fusion–positive lung cancer in both treatment-naïve patients and in those who were previously treated with a platinum-doublet chemotherapy. These data really formed the basis for the recent FDA approval of selpercatinib earlier this year.

Just recently, in September 2020, the FDA also approved pralsetinib for patients with RET fusion–positive lung cancer, as well.

How does the ARROW trial differ from LIBRETTO-001? How do these data help guide treatment decisions?

The ARROW study was similar to LIBRETTO; it was a phase 1/2 study evaluating pralsetinib. It had a dose-escalation portion and dose expansion component, [which] was in RET fusion–positive lung cancer, as well as medullary thyroid cancer and other RET fusion–driven malignancies. Pralsetinib showed very impressive tumor activity in patients with previously treated RET fusion–positive lung cancer, as well as previously untreated patients.

Both agents showed very promising data with respect to brain metastases. Both drugs appeared to show nice intracranial activity, as well. This highlights that when you have a very rare subtype of lung cancer—a rare subtype being 1% to 2% of patients—and if we can show very robust responses, even in a single arm study, that can be sufficient [enough] to lead to regulatory approval. [This is] because it's exceedingly challenging to do large studies in these rare patient populations.

The other lesson of both drugs is this tumor-agnostic approach, which is that RET fusions are found in multiple other tumor types and so, both agents have also shown activity outside of RET fusion–positive lung cancer, similar to the experience with NTRK [fusions], [which are] seen in multiple different tumor types. Also, underscoring that there are times where targeted therapies can be used in tumor agnostic fashion, as was shown here. It's important to actually to do this study to demonstrate that because we sort of have examples where that's not the case—the prime example there is BRAF. BRAF inhibition plus MEK inhibition is very active in colon cancer and lung cancer but less in [other malignancies].

In the METex14 arena, could you put the GEOMETRY mono-1 data into context?

METex14 is found in about 3% to 5% of all patients with lung cancer. It's important to first discuss the mechanism of oncogenic activation here because this alteration is a bit different than the others we've talked about. METex14 encodes the civil binding domain of MET, which is typically targeted for ubiquitin mediated degradation. When that site is lost, you don't get the same level of recycling of MET, it can lead to excess MET signaling, and then that serves as an oncogenic driver.

The GEOMETRY mono-1 study was looking at the role of capmatinib (Tabrecta) in patients with METex14 skipping, as well as MET amplification. Capmatinib is a novel MET inhibitor that is seen as highly penetrant. What we saw in that study were very nice responses in patients with metastatic METex14 skipping NSCLC, particularly in the first-line setting. In the subgroup of patients who were treatment naïve, we saw very robust responses with an objective response rate of more than 60% in the first-line setting. These data form the basis for the recent FDA approval of capmatinib for patients with METex14 skipping. [These data are] very exciting, [providing] another FDA approval and another therapeutic target.

What other molecular targets under exploration do you think have therapeutic potential?

One area that the whole oncology community is excited about is the KRAS space, specifically KRAS G12C. About 40% to 50% of KRAS mutations in lung cancer affect our G12C alterations. We’ve known about KRASalterations in lung cancer for decades, but have been unable to target it. It has been remarkably frustrating because it is 1 of the most common molecular alterations in lung cancer. Several years ago, though, it was recognized that KRAS G12C creates a novel binding pocket for these allosteric inhibitors.

There are 2 allosteric inhibitors that have entered clinical trials that have been, on first pass, very encouraging. [The early data show] proof of principle that if you can give a KRAS G12C inhibitor, you can induce tumor responses in lung cancer. Those are some of the data that I'm most interested to see. We are evaluating these compounds in larger patient populations, as well as trying to get a better sense of the durability of these responses.

The other molecular target with ongoing interest is for patients with HER2 mutations. HER2 mutations are seen in a small subset of patients with lung cancer. Using TKIs hasn't been a very successful strategy so far, but we've seen more encouraging data with antibody-drug conjugates, specifically at the 2020 ASCO Virtual Scientific Program. We saw some really exciting data with fam-trastuzumab deruxtecan-nxki (Enhertu), which showed a response rate of more than 60%.

References

1. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed October 6, 2020. https://bit.ly/34JUV6t
2. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. September 4, 2020. Accessed September 16, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions