RET, MET Inhibitors Advance Targeted Therapies in NSCLC

Vivek Subbiah, MD

FDA approvals of novel agents for molecularly defined subtypes of non–small cell lung cancer (NSCLC) are poised to change both patient outcomes as well as pretreatment testing requirements for those harboring these tumors.

In 2020, the agency approved biomarker-specific therapies for patients whose NSCLC tests positive for RET fusions or MET exon 14 mutations, marking a big breakthrough for patients with these aberrations. Although the proportion of patients with these genetic alterations is low—estimated at 1% for RET fusions and 3% to 4%, for MET exon 14 alterations—these groups are primed to experience significantly improved outcomes. In addition, data reported in 2020 about novel, investigational, target-specific therapies in NSCLC indicate that this list will continue to grow in the near future.

“The year 2020 has been phenomenal for us in NSCLC,” Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics Department, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, told Targeted Therapies in Oncology in an interview. “In May, we had a new FDA approval every week. I think 2021 and 2022 will also be good in this space.”

Edward B. Garon, MD, MS

RET Fusion–Positive NSCLC

Mutations in the RET gene have been difficult to target for investigators, according to Edward B. Garon, MD, MS, a health sciences associate clinical professor of medicine at David Geffen School of Medicine at UCLA in Los Angeles, California. “Until now, our main agents for these patients have been multitargeted tyrosine kinase inhibitors [TKIs], with limited effectiveness and high toxicities. There wasn’t much enthusiasm [among investigators] until recently in terms of available therapy for this patient population. But now we do have good treatment options for this population.”

Selpercatinib In May, the RET inhibitor selpercatinib (Retevmo) became the first biomarker-specific therapy to earn FDA approval for RET fusion–positive NSCLC. The approval was based on the results of the open-label phase 1/2 LIBRETTO-001 trial (NCT03157128), which were published in the New England Journal of Medicine in August with Subbiah as senior author.^1,2

The trial explored selpercatinib in both pretreated and treatment-naive patients with advanced RET fusion–positive NSCLC across 65 centers in 12 countries. The primary end point was the objective response rate (ORR) as determined by an independent review committee. Secondary end points included the duration of response (DOR).

Initial enrollment consisted of 105 patients with pretreated RET fusion–positive advanced NSCLC who received treatment across both the phase 1 dose-escalation portion of the trial (n = 49) and the phase 1 dose-expansion or phase 2 portion of the trial (n = 56). Additionally, the investigators later enrolled 39 previously untreated patients with the same malignancy type.

Among pretreated patients with RET fusion–positive NSCLC, nearly two-thirds (64%) responded to treatment per blinded independent central review. Two patients achieved a complete response (CR), 62% had a partial response (PR), and an additional 29% had stable disease (SD). At a median follow-up of 12.1 months, 63% of the responses were ongoing. The median DOR was 17.5 months (95% CI, 12.0-not evaluable [NE]).

Among the 39 previously untreated patients, 85% responded to treatment (95% CI, 70%-94%), and 90% of these responses continued at 6 months. Responses in this cohort comprised PRs exclusively, and 10% of patients had SD. The median duration of response was not yet reached (95% CI, 12.0 months-NE).

Eleven patients had baseline central nervous system metastases at enrollment, and nearly all of them experienced an intracranial ORR (91%; 95% CI, 59%-100%). This included 3 patients with CRs (27%), as well as 7 patients with PRs (64%). The remaining patient had SD. The median CNS DOR was 10.1 months (95% CI, 6.7-NE).

“Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC,” Subbiah said. “Our data clearly show that patients benefitted from this treatment.”

Pralsetinib

Patients with RET fusion–positive NSCLC may also be treated with the selective RET kinase inhibitor pralsetinib (Gavreto), which gained accelerated approval from the FDA in September for the treatment of patients with RET fusion–positive NSCLC based on the global registrational phase 1/2 ARROW trial (NCT03037385), which is ongoing.³

The trial is examining pralsetinib in patients with advanced solid tumors and RET alterations, including RET fusion–positive NSCLC. Of 179 patients with RET fusion– positive NSCLC, 116 were evaluable at the data cutoff in November 2019, and results from this group of patients were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program (ASCO 2020).⁴

According to blinded independent central review, response-evaluable patients had an ORR of 65% (95% CI, 55%-73%). Six percent of evaluable patients achieved a CR and 59% experienced a PR. Among treatment-naïve patients (n = 26), the ORR was 73% (95% CI, 52%-88%), with a 12% CR and a 62% PR rate. Among 80 patients who had been pretreated for NSCLC, the ORR was 61% (95% CI, 50%-72%), with 5% CRs and 56% PRs.

The investigators found that 96% of evaluable patients had tumor reductions, including 100% of patients who were treatment naïve.

The median duration of response was not reached (NR; 95% CI, 11.3 months-NR). Of the pretreated patients, 80% of responding patients had responses lasting at least 6 months. Among treatment-naïve patients, 58% of responding patients had responses lasting 6 months or longer. At the time of presentation, 75% of responding patients were still on treatment.

Nine patients had measurable central nervous system metastases at baseline. Blinded central reviewers found that the intracranial ORR was 56%. Additionally, 3 of these patients obtained an intracranial CR.

“Patients have had beautiful responses to pralsetinib characterized by the resolution of all lesions, regardless of the presence of brain metastases, which is extremely uncommon in NSCLC,” Subbiah said. “These patients had no good treatment options before this approval.”

Capmatinib in MET-Dysregulated NSCLC

In May, the FDA approved capmatinib (Tabrecta), a selective inhibitor of the MET receptor, for use in patients with NSCLC tumors harboring MET exon 14 skipping mutations or MET amplifications. Approval was based on the multicohort phase 2 Geometry Mono-1 trial (NCT02414139), the results of which were published in the New England Journal of Medicine in September.^5,6

The trial evaluated capmatinib in 364 patients with MET-dysregulated advanced NSCLC. Investigators assigned patients to cohorts based on their previous lines of therapy and MET status. ORR was the primary end point and DOR was a key secondary outcome measure, both assessed by blinded central review.

In patients with MET exon 14 skipping mutations, reviewers identified a response in 41% of pretreated patients (n = 69; 95% CI, 29%- 53%). Among those who were treatment naive (n = 28), 68% (95% CI, 48%-84%) responded to treatment. The median DOR was 9.7 months (95% CI, 5.6-13.0) among pretreated patients and 12.6 months (95% CI, 5.6-NE) among treatment-naive patients.

The investigators observed limited efficacy among previously treated patients with MET amplification who had a gene copy number less than 10 (overall response in 7% to 12% of patients). Among pretreated patients with MET amplification and a gene copy number of 10 or higher, nearly one-third of patients responded to treatment (29%; 95% CI, 19%-41%). Among patients without prior treatment, 40% experienced a response (95% CI, 16%-68%).

Garon, who was one of the investigators on the Geometry Mono-1 trial, appreciated the opportunity to study the role of MET as an oncogenic driver. “The fact that this trial evaluated both amplification as well as the exon 14 skipping mutation gave us a broader understanding of the role of MET as a biomarker in lung cancer,” he said. “One question that remains is whether this is an agent to use in the frontline setting. I would argue the data are not entirely clear, partly because we don’t know how well this patient population does with standard therapies.”

Looking Ahead

Meanwhile, work continues to explore the potential applicability of targeted therapies for oncogenes that do not currently have available options for biomarker-specific application. Promising trials abound, but no FDA approvals have yet materialized for either HER2- or KRAS-positive NSCLC.

Trastuzumab deruxtecan

Trastuzumab deruxtecan (T-DXd; Enhertu) is a novel antibody-drug conjugate that consists of 3 components: a humanized, anti-HER2, IgG1 monoclonal antibody and a topoisomerase I inhibitor payload that are connected by a tetrapeptide-based cleavable linker. Results of the open-label, multicohort phase 2 DESTINYLung01 trial (NCT03505710) exploring the agent in patients with HER-positive tumors were presented at ASCO 2020.⁷

Patients enrolled in the trial must have received no prior HER2-targeted therapies, with the exception of pan-HER TKIs. ORR confirmed by an independent central committee was the primary end point. One cohort consisted of patients who had HER2-expressing tumors; the other included patients whose tumors harbored a HER2 mutation

At data cutoff in November 2019, the ORR in 26 patients confirmed by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient had a CR (2.4%), 25 had a PR (59%), and an additional 12 patients had SD (28.6%). With only 2 patients either having progressive disease or being NE, the disease control rate was 90% (95% CI, 77.4%- 97.3%). The median DOR was not reached. The median follow-up was 8.0 months (range, 1.4-14.2 months) and the median duration of exposure to the drug was 7.8 months.

Investigators have expanded enrollment by 50 patients in the HER2-mutated cohort to better characterize the risk-benefit ratio of T-DXd. The FDA awarded T-DXd a breakthrough therapy designation in May for metastatic HER2-mutated NSCLC based on these data.⁸

Garon noted that HER2 has been a difficult therapeutic target to date in NSCLC. “Unlike in breast cancer, [in which] HER2 tends to be amplified, in lung cancer there tends to be specific mutations. They tend to be in exon 20, which is somewhat structurally analogous to exon 20 mutations in EGFR, which have traditionally been a difficult target for drugs,” he said. “But the DESTINY-Lung01 data to date have been quite as promising in a population that is somewhat difficult to treat.”

Sotorasib

Long considered undruggable, KRAS mutations are believed to account for about 13% of NSCLC cases. Sotorasib, a small molecule that selectively and irreversibly targets KRAS G12C, is considered a promising therapy. A variety of clinical trials are currently underway under the CodeBreak clinical trial umbrella.

In the phase 1 CodeBreak 100 trial (NCT03600883), results of which appeared in the New England Journal of Medicine, investigators enrolled 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) in dose-escalation/-expansion cohorts.⁹

The investigators observed no dose-limiting toxic effects or treatment-related deaths. In the subgroup with NSCLC, nearly one-third of patients (32.2%) had a confirmed objective response, whereas 88.1% of patients (n = 52) had disease control. The median progression-free survival was 6.3 months (range, 0.0-14.9).

More recently, Amgen has announced positive topline phase 2 results for sotorasib in a press release. Calling the trial “potentially registrational,” the company said that detailed results will be released at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer in January 2021.¹⁰

Meanwhile, CodeBreak 200 (NCT04303780), a global, phase 3, randomized, active-controlled confirmatory study comparing sotorasib to docetaxel in KRAS G12C–mutant NSCLC, has begun recruiting. Investigators shared complete study details in a poster at the European Society for Medical Oncology Virtual Congress 2020.¹¹

“The fact that KRAS is now druggable has opened up our field,” Subbiah said. “With the phase 3 trial enrolling more than 500 patients in its first 6 months, I won’t be surprised if there’s a 2021 approval in store for us.”

_References:

_{1. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed November 14, 2020. https://bit.ly/2K7qf8n}

_{2. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-24. doi:10.1056/NEJMoa2005653}

_{3. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. Updated September 8, 2020. Accessed November 14, 2020. https://bit.ly/3kFME9w}

_{4. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515}

_{5. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. FDA. May 6, 2020. Accessed November 14, 2020. https://bit.ly/2Uy6hpm}

_{6. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787}

_{7. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504}

_{8. Enhertu granted breakthrough therapy designation in the US for HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca. May 18, 2020. Accessed November 16, 2020. https://bit.ly/3kMoDhe}

_{9. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239}

_{10. Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer. News release. Amgen. October 5, 2020. Accessed November 16, 2020. https://bit.ly/3f9rkbt}

_{11. Reck M, Spira A, Besse B, et al. CodeBreak 200: a phase III, multicenter study of sotorasib (AMG 510), a KRAS(G12C) inhibitor, versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutation. Ann Oncol. 2020;31(suppl 4):S894-S895. doi:10.1016j.annonc.2020.08.1730}