Efforts Expand for Targeting Rare Alterations in NSCLC

Kristi Rosa

Karen L. Reckamp, MD, medical director, Clinical Research Operations, City of Hope Comprehensive Cancer Center

Karen L. Reckamp, MD

The list of less-common targetable mutations that are under investigation in non–small cell lung cancer (NSCLC) continues to expand, according to Karen Reckamp, MD, MS, and several novel therapies developed for these alterations have either already received regulatory approval or are showing promise in clinical trials.

“[There are] targetable mutations and alterations in NSCLC [beyond] what we call ‘the big 3,’ or EGFR, ALK, and ROS1,” said Reckamp. “There’s a growing list of tumor mutations and gene alterations [in this space], specifically BRAF, NTRK, RET, MET, and KRAS. For 2 of those [alterations], BRAF and NTRK, [there are] approved drugs available, and [the others] have drugs that are under exploration in clinical trials.”

In June 2017, the FDA approved the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) for patients with advanced or metastatic NSCLC who harbor BRAF V600E mutations, a subset of patients who have historically been known to have a poor prognosis.

In November 2018, larotrectinib (Vitrakvi) was granted an accelerated approval by the FDA for use in adult and pediatric patients with solid tumors that possess an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative options or have progressed following treatment.

Most recently, in August 2019, the FDA granted an accelerated approval to entrectinib (Rozlytrek) for use in adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion; it was also approved for adults with metastatic NSCLC whose tumors harbor a ROS1 alteration.

Additional agents are making their way through the pipeline for use of other lesser-known targetable alterations in NSCLC, said Reckamp.

For example, for treatment-naïve patients with locally advanced or metastatic MET exon14 skipping (METex14)–altered NSCLC, the MET inhibitor capmatinib demonstrated an objective response rate (ORR) of 67.9% (95% CI, 47.6%-84.1%), as assessed by independent review, according to primary data from the phase II GEOMETRY mono-1 trial. These data let to the FDA’s decision to grant a priority review designation to a new drug application (NDA) for capmatinib in this setting.1

Additionally, findings from the phase II VISION trial showed that the MET inhibitor tepotinib led to an ORR of 50.0% via independent review and an investigator-assessed ORR of 55.3% in patients with METex14-altered NSCLC. Based on these data, the FDA granted tepotinib a breakthrough therapy designation as a treatment for patients with metastatic NSCLC with METex14 alterations who have progressed on prior platinum-based chemotherapy.2

In those with RET fusion–positive NSCLC, pralsetinib (BLU-667) was found to induce an ORR of 61% (95% CI, 50%-72%),3 and the ORR reported with selpercatinib (LOXO-292) was even higher, at 68%.4 In January 2020, the FDA granted a priority review designation to an NDA for selpercatinib for the treatment of patients with advanced RET fusion–positive NSCLC, RET-mutant medullary thyroid cancer, and RET fusion–positive thyroid cancer.

“These drugs are more targeted specifically to RET and appear to have promising activity, even in the brain,” said Reckamp.

One of the most prevalent mutations in NSCLC is KRAS, according to Reckamp, and inhibitors have been designed to target a subset of patients who harbor KRAS G12C mutations. The furthest along in development is AMG 510, which elicited a 100% disease control rate at the target dose in evaluable patients, according to results from a small, first-in-human trial.5 The FDA granted a fast track designation to AMG 510 in September 2019 for the treatment of patients with KRAS G12C–mutated NSCLC who have received prior therapy, based on the early findings.

In an interview during the 2020 OncLive® State of the Science Summit on Lung Cancer, Reckamp, professor, director of the Division of Medical Oncology, medical oncology director of the Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, and associate director for Clinical Research, Cedars-Sinai Cancer, highlighted the different agents that have been developed to target rarer abnormalities in NSCLC.

OncLive: What are some of the rarer mutations being explored as targets in NSCLC?

Reckamp: BRAF is probably one of the most prominent [less-common mutations], and it’s more commonly found in smokers. [There are] approved drugs [for those whose tumors harbor this mutation]. For example, dabrafenib combined with trametinib, which has shown an ORR of about 60% and a median progression-free survival of about 10 months for patients who receive that combination.

Approved drugs are also available [for those with NTRK abnormalities]; this is an exceedingly rare tumor alteration found in lung cancers; less than 1% of patients’ [tumors harbor it]. The 2 drugs that are available are larotrectinib and entrectinib, which have ORRs of around 70%. The important aspect [to note with regard to] exceedingly rare target is this: If you do not do comprehensive genomic testing, you won't find these alterations. As such, comprehensive genomic testing is incredibly important for our patients with NSCLC.

How has the use of MET as a target evolved over the years?

MET, as a target, is very heterogenous; there are MET amplifications and METex14 mutations. Multiple MET inhibitors in the clinic are multi-targeted inhibitors, and many [of these agents] are under investigation at this time. METex14 appears to be a very viable target and early studies [with targeted therapies] have shown responses in these patients. With MET amplification, it's harder to identify what the correct ‘cut point’ should be. MET amplification can be seen as a primary alteration and can also be seen as a mechanism of resistance, such as in patients with tumors that harbor EGFR mutations. [We] are [faced with] complex issues when we think about MET amplification, but as far as METex14 [mutations] go, I believe that it's a very viable marker. Also, the MET inhibitors, capmatinib and tepotinib, are both [being examined] in clinical trials [and are] inducing responses in patients with this alteration.

Could you expand on some of the work being done with capmatinib and tepotinib?

[Capmatinib and tepotinib] are promising drugs for [those with] METex14 alterations. In the clinic, we now have capmatinib, which has shown responses in patients who have not received prior MET inhibition.

Another drug is tepotinib, which has also been shown to induce responses in patients. Interestingly, [investigators] have allowed for patients with METex14 [alterations] identified by blood or by tissue [on to the trial examining tepotinib]. That becomes incredibly important because these patients tend to be older and potentially have more comorbidities. As such, if tumor tissue is not sufficient, then it looks like blood testing [can be used to find] METex14 [mutations and] will result in similar outcomes.

What work is being done to target RET fusions in NSCLC?

RET fusions are found in a small percentage [of patients with] lung cancer, but 2 drugs have shown incredible promise. We have tried [to use multi-targeted TKIs] in the past to treat patients with RET alterations, [but we didn’t see] a significant response rate [with those agents]—just modest [activity]. We now have pralsetinib, which has about a 60% ORR and then also selpercatinib, which also has about a 70% ORR.

Could you discuss the potential with AMG 510 for patients with KRAS G12C-mutant NSCLC?

KRAS is a target that has alluded us for decades; it is one of the most prevalent mutations in NSCLC; about 25% of [tumors harbor it]. A subset of these patients have KRAS G12C [mutations]; we now have specific inhibitors of KRAS G12C [to treat them]. The [agent for which the] most data that are available is AMG 510, and this inhibitor has recently shown response rates of about 48% [in patients with lung cancer].


  1. 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.           
  2. Pail PK, Veillon 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.
  3. Blueprint Medicines announces top-line data for pralsetinib and initiates rolling NDA submission to FDA for the treatment of patients with RET fusion–positive non-small cell lung cancer [news release]. Cambridge, MA: Blueprint Medicines; January 8, 2020. bit.ly/39zvF3r. Accessed February 14, 2020.
  4. 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. J Thor Oncol. 2019;14(suppl 10; abstr PL02.08):S6-S7. doi: 10.1016/j.jtho.2019.08.059.
  5. Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS G12C inhibitor, evaluated in NSCLC. J Thor Oncol. 2019;14(suppl 10; abstr OA02.02):S208. doi: 10.1016/j.jtho.2019.08.412.
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