Over the last decade, we have witnessed significant advances in the treatment of advanced non-small cell lung cancer (NSCLC) through the joint revolutions of targeted genomic therapy and immunotherapy. We now have multiple effective therapeutics for metastatic NSCLC patients in the front-line setting that offer proven and durable clinical benefit compared to platinum doublet chemotherapy. As our tool set of therapeutics expand, so has the development of predictive and prognostic biomarkers. These biomarkers have been crucial in better defining subsets of NSCLC and directing optimal therapeutics in these more defined subsets. Currently, the main biomarkers in NSCLC that predict therapeutic efficacy include driver oncogene alterations detected by next-generation sequencing (NGS), such as ALK, ROS1, and NTRK fusions, sensitizing EGFR mutations, RET rearrangements, MET exon 14 skipping mutations, and BRAFV600E mutations, and immune profiling with immunohistochemistry for Programmed death ligand-1 (PD-L1) expression level.
For NSCLC patients with sensitizing driver mutations in oncogenes detected by NGS, matched kinase inhibitors offer excellent response rates and often with minimal toxicity. For NSCLC patients without driver mutations, immunotherapy with immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD-1) or its ligand (PD-L1) offer improved overall survival, especially in patients with high PD-L1 expression, driven by the subset of patients that achieve remarkable durable responses. Despite our significant advancements, many questions remain, and among them being the optimal combination and sequencing of efficacious therapies.
BRAFV600E targeted therapy in NSCLC
Mutations in BRAF, an oncogene in the RAF kinase family that is part of the canonical MAPK signaling cascade (downstream of RAS and upstream of MEK) involved in cell growth and proliferation (1), are detected in 2–4% of NSCLC patients. The most common BRAF mutation in NSCLC and other cancers is the V600E mutation in exon 15 representing approximately 50% of BRAF mutations in NSCLC and in general mutually exclusive with other NSCLC driver oncogene mutations such as EGFR, KRAS, ALK, ROS1, MET, and RET alterations (2). Unlike EGFR, ALK, ROS1, and RET alterations which are generally found in non-smokers, BRAFV600E mutations can be found in both smokers and non-smokers with conflicting findings from retrospective series, but on the whole favoring a slight enrichment of former and current smokers and a slight female predominance (2).
The BRAFV600E mutation leads to constitutive activation of the kinase and the promotion of cell proliferation mediated by downstream signaling through MEK and ERK. Multiple potent BRAF inhibitors (BRAFi), such as vemurafenib, dabrafenib, and encorafenib, have been developed against activated BRAFV600E and extensively studied in melanoma, where activating BRAFV600E mutations represent the majority (~70–80%) of BRAF mutations found in approximately 40% of metastatic melanoma patients. Monotherapy with first and second generation selective BRAFi demonstrated clinical response in BRAFV600E mutated metastatic melanoma, but had somewhat limited efficacy due to acquired resistance as well as adverse events, particularly the development of secondary malignancies due to paradoxical MAPK activation through upstream RAS (3). The combination of MEK inhibitors (MEKi), such as trametinib, binimetinib, and cobimetinib, with BRAFi can delay the emergence of resistance and decrease adverse events due to paradoxical MAPK activation, and multiple phase III clinical trials have demonstrated combination BRAFi and MEKi as significantly more efficacious than single agent BRAFi in BRAFV600E mutant metastatic melanoma patients with overall response rates (ORR) of 64–68%, median progression free survival (PFS) of 11.1–14.9 months, and median overall survival (OS) of 22.3–33.6 months (4). The combination of BRAFi with MEKi is now established as the standard of care targeted therapy regimen in BRAFV600E mutated metastatic melanoma.
Extending the clinical use of targeted therapies against BRAFV600E mutations from melanoma to NSCLC, a retrospective study of 35 European BRAF-mutant (>80% V600E) NSCLC treated with BRAFi monotherapy showed an ORR of 53%, PFS of 5.0 months, and median OS of 10.8 months suggesting clinical benefit of BRAFV600E targeted therapy in NSCLC (5). A basket trial evaluating monotherapy with vemurafenib in a variety of BRAFV600 mutated cancers demonstrated a 42% ORR and PFS of 7.3 months in 19 BRAFV600 mutant NSCLC patients (6). A recent French study of vemurafenib monotherapy in NSCLC showed similar results in 96 BRAFV600E mutant NSCLC patients with an ORR of 44.8%, median PFS of 5.2 months, and median OS of 10 months (7).
The prospective evaluation of dabrafenib monotherapy in BRAFV600E mutant NSCLC in an open-label, multicenter, phase 2 trial also demonstrated some clinical activity with ORR of 33% and a median PFS of 5.5 months, and OS of 12.7 months in 78 previously treated patients (8). Two additional cohorts in this phase 2 dabrafenib trial evaluated the BRAFI and MEKi combination of dabrafenib and trametinib in previously treated and in untreated NSCLC patients, and showed a more substantial and durable responses that lead to the FDA approval in 2017 of the combination of dabrafenib and trametinib for NSCLC patients with BRAFV600E mutations. In the previously treated cohort of 57 BRAFV600E mutant NSCLC patients, dabrafenib plus trametinib treatment demonstrated a 63% ORR, PFS of 9.7 months, and OS of 18.2 months (9). In the front-line cohort of 36 BRAFV600E mutant NSCLC patients, combination dabrafenib plus trametinib treatment demonstrated a similar ORR of 64% with longer PFS of 10.9 months and a remarkable median OS of 24.6 months (10). Treatment was tolerated in both previously treated and untreated cohorts, with a 12–22% rate of adverse events that lead to discontinuation. Similar open-label phase 2 studies are currently evaluating the combination of encorafenib with binimetinib in BRAFV600E mutant NSCLC in front-line and second-line settings. Currently, the NCCN panel recommends the dabrafenib and trametinib combination as the preferred first-line systemic option in metastatic NSCLC with BRAFV600E mutations.
Immunotherapy in PD-L1 high NSCLC and BRAFV600E NSCLC
The development of ICI targeting PD-(L)1 has revolutionized the treatment of metastatic NSCLC and ICI have quickly emerged as a near universal component in front-line treatment of metastatic NSCLC without driver oncogene mutations. The phase III open-label KEYNOTE-024 demonstrated the use of PD-L1 expression levels as a biomarker to select for patients who can be treated successfully with front-line ICI monotherapy. In metastatic NSCLC patients with high PD-L1 expression (tumor proportion score, TPS ≥50%) without EGFR sensitizing mutations or ALK fusions, pembrolizumab monotherapy demonstrated superior median OS of 30.0 months compared to 14.2 months with platinum doublet chemotherapy (11). NSCLC patients with high levels of PD-L1 expression also derived significant benefit of the addition of ICI to chemotherapy, with the PD-L1 high subset in the phase 3 randomized KEYNOTE-189 trial demonstrating an ORR of 62.1% to combination chemotherapy with ICI and a 51.9% 24-month survival (12).
Efforts to extend the benefit of these remarkable durable responses from ICI treatment to genomic subsets of NSCLC has not been straightforward, especially in the largest genomic subset of sensitizing EGFR mutant NSCLC. Meta-analysis of second-line ICI in NSCLC trials did not show a survival benefit of ICI compared to chemotherapy in EGFR mutant NSCLC (13). The prospective ATLANTIC trial evaluating durvalumab in the third-line setting showed lower response rates in the combined EGFR and ALK mutant cohort compared to cohorts lacking EGFR and ALK mutations (14). Similarly, the phase II trial of pembrolizumab in PD-L1 positive, EGFR mutated NSCLC was terminated early due to lack of response in the initial 11 patients (15). These findings resulted in the exclusion of EGFR and ALK patients from many front-line ICI clinical trials. Whether these findings in EGFR mutant NSCLC extend to other oncogene driver subsets in NSCLC such as BRAFV600E remains unknown. Also unknown is whether the benefit of ICI in front-line extends to genomic subsets given the lack of selection or stratification for other oncogene drivers in the large, pivotal ICI trials in NSCLC. Given the 1–2% prevalence of BRAFV600E in NSCLC, only a handful of patients were likely enrolled in each of the front-line ICI studies, limiting our interpretation of the effectiveness of front-line ICI in BRAFV600E mutant NSCLC.
The IMMUNOTARGET retrospective study of 551 NSCLC patients with known oncogenic driver alterations treated with single-agent ICI demonstrated a range of response rates and PFS in different oncogene alterations with 0% and 12% ORR in ALK and EGFR mutant subsets respectively compared to 26% ORR in KRAS mutant subsets (16). This perhaps speaks to the different clinical pathologic characteristics of different mutation subsets. The BRAF mutant subset, which included n=17 V600E mutants and n=18 non-V600E mutants, demonstrated a 24% ORR comparing similarly to the KRAS mutant subset. On univariate analysis in BRAF mutants, the V600E subset trended towards a lower PFS (1.8 months) compared to non-V600E BRAF mutants (4.1 months), no difference in PFS between number of previous lines of treatment, and a significantly higher PFS was noted in smokers compared to never smokers (4.1 vs. 1.9 months, P=0.03) (16).
Another small retrospective study by Dudnik et al. evaluated PD-L1 status and response to ICI in a cohort of 39 BRAF mutant NSLC patients (n=21 with V600E mutations and n=18 with non-V600E mutations) treated with ICI (17). In this cohort, non-V600E BRAF mutant patients were significantly enriched for smokers (78% smokers) compared to BRAFV600E mutant patients (43% smokers). Of the 39 patients, 29 were tested for PD-L1 expression and higher rates of high PD-L1 expression (TPS ≥50%) were found in BRAF mutants compared to the expected 30% prevalence in unselected NSCLC, with 42% of BRAFV600E mutants with high PD-L1 expression and 50% of BRAFnon-V600E mutants with high PD-L1 expression. However, given the limited number of patients, and some evidence that PD-L1 expression in oncogene-mutated NSCLC may be more reflective of aberrant oncogene signaling rather than predictive of immune engagement, it remains to be seen if PD-L1 expression is predictive of ICI response in BRAFV600E mutant NSCLC. Response rates to ICI in this cohort were similar to the IMMUNOTARGET cohort with 25% ORR in BRAFV600E mutant patients and 33% ORR in BRAFnonV600E mutant patients.
These two retrospective studies do suggest that at least some BRAFV600E mutant NSCLC respond to ICI treatment, with the subset (especially in smokers) perhaps more similar to KRAS mutant subset than EGFR/ALK subset in terms of ICI response and the response rates of 24–25% compares favorably to second line ICI trials in unselected NSCLC. Given the decrease in efficacy of ICI in non-smokers compared to smokers, it seems likely that driver mutation subsets that are enriched for non-smokers would have lower rates of response to ICI, while subsets such as KRAS and BRAF mutant NSCLC that harbor significant amount of smokers may contain more patients that are sensitive to ICI.
Sequencing of targeted therapy and immunotherapy in BRAFV600E NSCLC
In a metastatic BRAFV600E mutant NSCLC patient with PD-L1 >90% TPS, front line combination BRAFi and MEKi treatment with dabrafenib and trametinib, ICI monotherapy, or ICI combined with chemotherapy would all be appropriate FDA approved front-line treatment options, with no prospective head to head clinical trials to help choose the best front-line option. Given the similarities with available treatment options in BRAFV600E mutated melanoma, it seems reasonable to gain insight from the debate in melanoma over the optimal sequencing of targeted therapy compared to ICI, while acknowledging that there are significant differences between melanoma compared to NSCLC both in tumor biology (with different distributions of BRAF mutations and where PD-L1 as a biomarker seems to have important clinical differences) as well as therapy options (where CTLA-4 blockade has been more commonly incorporated in melanoma compared to NSCLC therapy which includes chemotherapy combinations with ICI).
Initial retrospective studies of CTLA-4 blockade with ipilimumab in advanced melanoma patients with BRAFV600 mutations seemed to favor front line treatment with anti-CTLA4 prior to targeted therapy as response and outcomes to ipilimumab were better before targeted therapy compared to after targeted therapy (18). However, retrospective analysis of trials incorporating PD-(L)1 targeted therapies, which are perhaps more relevant to the NSCLC debate, suggest a more complicated picture. Given the different mechanisms of action of CTLA-4 blockade, which is postulated to act more centrally, compared to PD-1/PD-L1 blockade and BRAF/MEK inhibition both acting more directly intratumorally and in the tumor microenvironment, it should not be surprising to find differences with prior ipilimumab data. And since both PD-(L)1 blockade and BRAF/MEK inhibition both affect tumor signaling and the tumor microenvironment, there is a concern for overlapping toxicities as well as common mechanisms of resistance.
Pooled data from 4 clinical trials encompassing 106 BRAFV600 mutant melanoma patients showed similar response rates to nivolumab before (33.1%) and after (24.5%) BRAF inhibitor therapy (19). A larger pooled analysis of 3 pembrolizumab clinical trials encompassing 434 BRAFV600 mutant melanoma patients showed better response rates and better PFS to pembrolizumab in BRAFi naïve patients (ORR 44.2%, 4-year PFS 27.8%) compared to patients who received prior BRAFi with or without MEKi (ORR 28.4%, 4-year PFS 15.2) (20). Patients who received prior BRAF targeted treatment were patients with generally poorer prognosis with worse performance status, more PD-L1 negative tumors, more with prior ipilimumab treatment, higher LDH levels, and who had received more lines of treatment. While multivariate analysis still identified prior BRAF targeted therapy as associated with poorer response to pembrolizumab, there is no analysis of how patients do with BRAF targeted salvage therapy after pembrolizumab treatment in this study, and this poorer response may simply reflect patients with aggressive disease who share common mechanisms of resistance and who will respond poorly to both classes of therapy.
Indeed, a 2017 retrospective study of 114 BRAFV600 melanoma patients demonstrated that both PD-1 and BRAF targeted therapies were efficacious in the treatment naïve setting with similar OS and PFS, but both showed poorer efficacy as the salvage treatment, with ICI showing modest activity after prior BRAFi (25% ORR after BRAFi vs. 40% ORR in treatment naïve), but salvage BRAFi therapy after prior ICI showing the worst outcomes (21). It seems that there may be overlap in patients who benefit from both BRAFi and ICI or in patients with intrinsically aggressive disease who are resistant to both treatments, as patients who benefited from BRAFi therapy for more than 6 months had a higher ORR to subsequent ICI of 34% compared to 15% ORR to subsequent ICI in patients who had less than 6 months of benefit from BRAFi treatment (21). Another study looking at the combined analysis of survival curves grouped by type of systemic therapy in melanoma trials showed a superiority of combined BRAFi with MEKi compared to ICI in the first 6 months and then a gradual crossing of the curves perhaps speaking to the development of resistance and the more durable response of patients who respond to ICI (22). Given these two analyses, it seems a strategy of upfront BRAFi therapy followed by a switch to ICI may be a viable sequence, or a combination approach if toxicity can be managed. Two recent melanoma trials have demonstrated promise in combining BRAFi and MEKi with ICI with PD-(L)1 inhibitors (23). The phase 2 KEYNOTE-022 trial combining the triplet combination of pembrolizumab with full doses of dabrafenib and trametinib lead to significantly longer median PFS of 16.0 months compared to PFS of 10.3 months with doublet BRAFi/MEKi treatment at the cost of increased side effects with 25% discontinuation rate in the triplet therapy compared to 15% in the doublet. The phase 3 IMspire150 trial evaluated the addition of the PD-L1 inhibitor atezolizumab to BRAFi vemurafenib and MEKi cobimetinib using a modified dosing schedule that allowed for 28-day run-in of BRAFi and MEKi first prior to the addition of atezolizumab with a dose reduction in vemurafenib in the triplet combination arm. This study met its endpoint of improved PFS in the triplet atezolizumab combination of 15.1 months compared to 10.6 months with doublet BRAFi/MEKi with similar response rates and low rates of discontinuation due to adverse events (13% in triplet with reduced dose vemurafenib and 16% in doublet with full dose BRAFi/MEKi). Similar to the retrospective analysis of survival curves in Ugurul et al., in both KEYNOTE-022 and IMspire150 trials, the improvement in PFS curves also did not become evident until 7 months into treatment. We await the results of many prospective phase III trials in melanoma that are randomizing between different sequences and combinations of BRAFi/MEKi and ICI in the hopes of more definitive answers in optimal use of these agents.
In addition to concerns of similar mechanisms of resistance, there is also concern for increased toxicity in sequencing some kinase inhibitor therapies after PD-(L)1 therapy. Sequencing PD-(L)1 blockade prior to kinase inhibitor therapy with osimertinib in EGFR mutant NSCLC led to a high rate of severe immune mediated adverse events that was not seen with osimertinib treatment prior to ICI therapy (24). A retrospective study evaluating BRAFi/MEKi in melanoma patients previously treated with PD-1 based therapy also showed concerning rates of adverse events, with dose modifications seen in 84% of patients compared to the dose modification rates in ICI naïve settings which ranged from 33–61% (25).
Given the experience with other oncogene driver subsets in NSCLC that have favored the paradigm of targeted therapy first prior to ICI, especially with the increased risk of potential toxicities of BRAF targeted therapies after ICI, combined with the small amount of BRAFV600E mutant patients in front-line ICI studies compared to the larger prospective trial demonstrating durable efficacy of dabrafenib and trametinib combination in BRAFV600E mutated NSCLC, and the retrospective studies suggesting good response rates of second line and beyond ICI in BRAFV600E mutant NSCLC, it seems that even in the setting of high PD-L1 expression, the preferred initial treatment for a BRAFV600E mutant NSCLC should be targeted therapy.
Provenance and Peer Review: This article was commissioned by the Guest Editor Grace K. Dy for the series “Evidence and Controversies in the treatment of metastatic NSCLC” published in Precision Cancer Medicine. The article has undergone peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/pcm-2020-mnsclc-06). The series “Evidence and Controversies in the treatment of metastatic NSCLC” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: Yau EH. BRAFV600E mutant, PD-L1 TPS 90% NSCLC: 1st line treatment with targeted therapy. Precis Cancer Med 2021;4:10.