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Gregory J. Riely, MD, PhD, discusses targeted approaches for BRAF V600E, MET exon 14, and KRAS G12C mutations in metastatic NSCLC.
Targeted therapy continues to redefine treatment strategies for metastatic non–small cell lung cancer (NSCLC), particularly for tumors driven by BRAF V600E, MET exon 14–skipping alterations, and KRAS G12C mutations. During a presentation at the 20th Annual New York Lung Cancers Symposium®, Gregory J. Riely, MD, PhD, provided an in-depth overview of the biologic rationale and clinical evidence guiding the use of targeted agents across key oncogenic subsets, highlighting how efficacy and toxicity considerations intersect to inform real-world decision-making, and where additional research is still needed.
In his presentation, Riely expanded on the current clinical capability of targeting BRAF V600E mutations in NSCLC, with combined BRAF/MEK inhibition using dabrafenib (Tafinlar) plus trametinib (Mekinist) or encorafenib (Braftovi) plus binimetinib (Mektovi) serving as key targeted options, selected largely on the basis of toxicity considerations.1 He noted that MET exon 14–skipping mutations, more frequently seen in older adult patients and those with sarcomatoid tumors, are effectively treated with capmatinib (Tabrecta) or tepotinib (Tepmetko), while early activity with amivantamab (Rybrevant) appears limited following prior MET TKI therapy. He also highlighted the evolving role of KRAS G12C inhibitors, with sotorasib (Lumakras) supported by data from the phase 1/2 CodeBreaK 100 trial (NCT03600883) and adagrasib (Krazati) which was validated in the phase 1/2 KRYSTAL-1 trial (NCT03785249), both of which have reshaped second-line treatment as combination studies move into earlier lines of therapy.2,3
Riely currently serves as the Ning Zhao and Ge Li Chair in Lung Cancer Research and vice chair of Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York, New York.
Riely: It’s always important to remember that there are many types of BRAF mutations. If you talk to the basic scientists, they’ll tell you about classes 1, 2, and 3. The class 1 mutations are RAS-independent, signal-active monomers. Class 2 are RAS-independent, [constitutively] active dimers. Class 3 are RAS-[dependent]. BRAF V600 is the targetable oncogenic driver in patients with metastatic NSCLC, and so that’s what I’m talking about when I talk about BRAF.
We know that targeting BRAF is best done with combined inhibition of BRAF and MEK. This is a nice little signaling diagram that suggests to you that it’s very simple how signaling happens in a cancer cell that the BRAF V600 mutation leads to elevated MEK, leads to ERK, and all you do is inhibit both of those. Of course, it’s not that simple, but we do know from data in the melanoma world that combining BRAF and MEK leads to better outcomes. In patients with metastatic NSCLC, we have 2 combinations of BRAF and MEK inhibition that have been studied.
The first approved [combination] was dabrafenib/trametinib. Data [demonstrated] an overall response rate [ORR] of 68% and a median progression-free survival [PFS] of 11 months in the first-line setting. A similar combination of encorafenib with binimetinib was more recently approved with an ORR of 75% and a median PFS of 30 months in the first-line setting. Now these are both single-arm phase 2 trials, so [I] wouldn’t make a lot of the differences in efficacy that we saw, but these are the data that we have today.
When we think about combination BRAF and MEK inhibiton, one of the first things that comes to mind for most of us who practice is the toxicity. [We saw that] pyrexia, nausea, and diarrhea are very common in patients who receive dabrafenib/trametinib. [We] saw from the toxicity table from the seminal publication on dabrafenib/trametinib that pyrexia was the most common, with grade 3 occurring in 11% of patients, and lumped into the grade 1/2 section are lots of [instances of] nausea and diarrhea. You don’t need a lot of reminders to be know that grade 2 diarrhea is a significant problem if it happens every day. [This is] treatment that’s a constant oral therapy.
Encorafenib/binimetinib is a bit different [in terms of] toxicity profiles. Compared with dabrafenib/trametinib, the rate of pyrexia is somewhat lower. There was no treatment-related grade 3 pyrexia in the encorafenib/binimetinib trial. [We] saw some grade 1 and grade 2 pyrexia. There were similar rates of nausea and diarrhea for patients who received encorafenib/binimetinib vs patients who got dabrafenib.
I usually use encorafenib/binimetinib, because I was part of a phase 2 trial that looked at [it and] led to its approval, and I believe that the toxicity profile is slightly better and the efficacy data are certainly equivalent, if not better.
I’ll note that there are no randomized data comparing targeted therapy up front vs the use of chemotherapy or immunotherapy–chemotherapy combinations, and that’s a real omission. We do have some retrospective data. There are some data that were recently published [from] a large multicenter retrospective analysis that looked at outcomes on frontline therapies for patients with BRAF-mutated lung cancer.
[We] see here that the blue line is those patients who got checkpoint inhibitors with or without chemotherapy, and the red line is those patients who got targeted therapy. In general, these were patients who got dabrafenib/trametinib, and you see that the blue line is a little bit better than the red line. That certainly that there’s no detriment to receiving initial immunotherapy with or without chemotherapy.
There is also a forest plot that looked at which subgroups do best with targeted therapy [and] the ones that you would think about ahead of time are the ones that stand out. Patients who are never-smokers with BRAF mutations seem to do better with targeted therapy, as do patients with PD-L1–negative tumors. Based on this, it’s pretty clear that some patients should get targeted therapy [and] others may benefit from chemo-IO. We’d really benefit from a randomized trial. I’ll highlight that BRAF mutations occur approximately 1% of the time, and Dr Drilon’s talk next looks at another 1% mutation — RET — and in that context they did a randomized trial. We probably need randomized trials even in these relatively uncommon oncogenes.
MET exon 14 mutations happen in approximately 3% to 4% of patients with lung cancer. These are interesting mutations and the frequency changed from that slide to this slide; now it’s 4% to 5% of patients with metastatic NSCLC. Typically, this happens more commonly in elderly patients, and as you saw in the patient from Dr Ramos, there was [an] association with sarcomatoid histology.
I’ll note that the way MET exon 14 alterations work is that they stabilize the MET protein, so there’s increased expression of the MET protein — increased expression. The target of these drugs is normal wild-type MET in the cancer cell. That leads to some toxicities that are a consequence of targeting normal wild-type MET.
We have 2 FDA-approved agents for targeting MET exon 14–positive NSCLC. These are both data from single-arm phase 2 trials, so again, real space for a randomized trial in this context, but all we have are single-arm phase 2 trials looking at capmatinib and tepotinib. We see with capmatinib that the ORR was 68% and the median PFS was 12.5 months in the frontline setting. Similarly, for tepotinib in the frontline setting, the ORR was 57% and the median PFS was 12.6 months. I note that in patients with MET exon 14 alterations, second-line therapy has a lower response rate and a shorter median PFS, which again suggests that we should use these drugs in the first-line setting.
Both these drugs were approved several years ago, but there is something new happening. Amivantamab is being explored in patients with MET exon 14 alterations. It’s interesting because we saw an ORR of 15%, but the median PFS is relatively short at 5 months. Importantly, the ORR after a prior MET TKI is low, only 19%, so this is not your solution to resistance to MET TKIs.
For patients with MET exon 14 alterations, the standard initial therapy is a MET inhibitor, either capmatinib or tepotinib. I don’t have a real basis for distinguishing between these 2, so they’re both reasonable. A reminder again, there are no randomized data to tell us whether this is better than chemotherapy or immunotherapy and chemotherapy.
Approximately 25% of patients with lung cancer have KRAS-mutant disease, and half of the KRAS mutations are KRAS G12C. This is the most common alteration, next to EGFR, in patients with metastatic lung cancer. We’ve known about the ability to target KRAS G12C for over 10 years now, but only recently have we had clinically relevant drugs. The 2 drugs that we have in the clinic today are sotorasib and adagrasib. Both received their initial accelerated approvals based on the CodeBreaK and KRYSTAL trials.
They’ve both gone on to randomized trials that look a lot like [this]: they took patients with metastatic NSCLC who had prior chemotherapy and immunotherapy. Patients were randomly assigned to either docetaxel or KRAS G12C-targeted therapies, and the trials look very similar in terms of design and results. For sotorasib, we saw an ORR in the sotorasib arm of 28% vs 13% for docetaxel.
Int terms of PFS, the HR for sotorasib was 0.66. Similarly, for adagrasib, the ORR was 32%, and the HR for PFS was 0.58. Notably, in the sotorasib trial, which is the only one to report OS data, we haven’t seen an improvement in OS. This is somewhat disappointing, but I believe the improvements in toxicity make it [a] necessarily useful [option] in this context.
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