Targeted Therapies Emerging for Less-Common NSCLC Subtypes

Jessica Bauman, MD

Targeted therapies against EGFR mutations and ALK rearrangements have been associated with promising outcomes in non—small cell lung cancer (NSCLC), and recent data suggest that similar success is on the horizon for patients with BRAF, ROS1, and RET abnormalities, explained Jessica Bauman, MD.

“Slowly, we are starting to see activity with specific drugs, often oral drugs, that can target these mutations and create their own success story,” said Bauman, an assistant professor, Department of Hematology/Oncology, and associate program director,Hematology/Oncology Fellowship Training Program, Fox Chase Cancer Center.

In June 2017, the FDA approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients with BRAF V600—positive advanced or metastatic NSCLC. The approval was reported following the results of a phase II study.

At a median follow-up of 9 months, the overall response rate (ORR) was 61.1% in treatment-naïve patients (n = 36; 95% CI, 43.5%-76.9%) and 63% in previously treated patients (n = 57; (95% CI, 49%-76%). Durable responses were reported in this cohort, with a median duration of response of 12.6 months (95% CI, 6.9-16.0).

While Bauman said that targeted therapies are an “important and viable” therapeutic option for patients with BRAF mutations, she said she believes that immunotherapy has been left relatively unexplored in these patients and may offer an alternative treatment strategy. Patients with BRAF-mutant NSCLC also have higher levels of PD-L1 expression and tumor mutational burden, she added.

OncLive: Can you provide an overview of your presentation on BRAF-mutant, ROS1-rearranged, and RET-modified NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Bauman addressed current and emerging therapeutic options for patients with BRAF, ROS1, and RET abnormalities in NSCLC.Bauman: I spoke about some of the other targets in NSCLC that have become more important when thinking about new diagnoses of metastatic NSCLC. We spoke about BRAF, ROS1, and RET, all of which are associated with new targeted therapies. BRAF, ROS1, and RET are found in 1% to 5% of lung adenocarcinomas. We know that the classic success stories in lung cancer in the last decade have been with EGFR and ALK mutations.

Interestingly, we know that 60% of lung adenocarcinomas have mutations, which are likely involved in driving tumor growth. BRAF is a commonly seen mutation in melanoma but is seen in 1% to 5% of patients with NSCLC. In about 50% of those patients, we see V600E mutations. The drugs that have been approved in melanoma for many years have now shown activity in NSCLC. There are the recent data with dabrafenib and vemurafenib (Zelboraf) as single agents.

We’ve most recently seen the combination of dabrafenib and trametinib, which is a MEK inhibitor, with response rates [around] 60%. The combination has also shown very decent progression-free survival and duration benefits. Patients who have BRAF mutations can derive benefit from these targeted treatments. Targeted therapy has become a very viable and important option for patients with BRAF mutations, but we also know that these patients may respond better to immunotherapy.

There are a lot of questions about response to immunotherapy for patients with targetable mutations. However, patients with BRAF mutations have higher PD-L1 levels and TMB, and [these mutations] are more commonly found in smokers. Because of that, we still think immunotherapy plays an important role in this population.

The second population of patients we covered are those with ROS1 rearrangements. We know that these [rearrangements] are also commonly found in never-smokers. Crizotinib (Xalkori) is the [main] treatment of choice for this population, but there are also several other up-and-coming treatments for this population as well. [We use] lorlatinib for patients with resistant disease. There are going to be a lot more data coming out in terms of new targeted therapies for patients with ROS1 mutations.

Could patients still benefit from BRAF monotherapy?

Are there any other BRAF/MEK combinations in development, such as binimetinib (Mektovi) and encorafenib (Braftovi)?

The last part we covered was patients with RET fusions. RET inhibitors show some activity in patients with NSCLC and RET fusions. We’ve seen activity with both cabozantinib (Cabometyx) as well as vandetanib (Caprelsa). There are 2 new RET inhibitors that were recently presented at the 2018 AACR Annual Meeting and 2018 ASCO Annual Meeting, which were LOXO-292 and BLU-667. These drugs are highly selective RET inhibitors and both agents showed very impressive responses. There is promising activity in treatments for our patients with these rarer mutations.In general, that’s done away with now. The toxicity profile with a BRAF and MEK combination is not higher [than BRAF monotherapy]. In fact, it is better tolerated. There’s also an increase in skin squamous cell carcinomas with single-agent BRAF inhibition. You don’t see that when you use a MEK inhibitor in addition [to a BRAF inhibitor]. That’s true in melanoma as well as in lung cancer. Dual blockade [with a BRAF and MEK inhibitor] is now FDA approved and is listed in the National Comprehensive Cancer Network guidelines.Some of these data are fairly new. I certainly think that people are looking at combinations. However, there are other things that will be more important to look at, such as the role of immunotherapy.

For patients with ROS1-rearranged NSCLC, what data do we have with lorlatinib?

What does the future landscape hold?

Patients with BRAF mutations have really amazing responses to immunotherapy. They’re the “tail of the curve.” If these patients have great responses to immunotherapy, targeted therapy may start to become more obsolete. For that population in particular, there’s going to be a lot that we need to understand about how to sequence targeted therapy and immunotherapy. Interestingly, that has become very relevant in terms of how to sequence BRAF inhibitors and immunotherapy in melanoma.The only data that have been published thus far is the original phase I trial with ALK- and ROS1-positive [patients]. On that trial, there were 12 patients who had ROS1 rearrangements. For those patients we saw a 50% response rate, which is quite high as well as a significant duration of response. There is certainly activity with lorlatinib in ROS1-rearranged NSCLC. We know that there is more to come from that trial.It is a great time to be a thoracic oncologist because we have more treatments available for our patients than we have ever had before. With molecular testing, we have turned lung cancer into personalized medicine. Lung cancer [does not have] a one-size-fits-all [approach]. We have to understand that the biology of lung cancer is very different from tumor to tumor. Telling a patient that is really helpful in helping them understand why they got lung cancer. The fact that we have real treatments that will give them real [improvements in] quality of life and more time with their families is very important.

Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34 (suppl; abstr 107).