Introduction
NSCLC is a genetically heterogeneous disease, of which several distinct oncogene-addicted populations have been identified. One of these lung cancer populations is
BRAF mutation-positive lung cancer, present in 2% to 3% of patients with advanced NSCLC.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,2- Tabbò F.
- Pisano C.
- Mazieres J.
- et al.
How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC).
BRAF (v-RAF murine sarcoma viral oncogene homolog B) mutations do not seem to be strongly associated with never-smoking histories, younger age, or Asian ethnicity, as is the case in some other forms of oncogene-driven NSCLC.
3- Ferrara M.G.
- Di Noia V.
- D’Argento E.
- et al.
Oncogene-addicted non-small-cell lung cancer: treatment opportunities and future perspectives.
BRAF mutations are categorized into three main classes (I–III) on the basis of RAF kinase activity and signaling. The V600E mutation is synonymous with the class I alteration which functions as a kinase-activated, RAS-independent monomer, whereas classes II and III are known as non-V600E mutations and function as kinase-activated, RAS-independent dimers and kinase-impaired, RAS-dependent heterodimer ERK pathway amplifiers, respectively.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,4- Dagogo-Jack I.
- Martinez P.
- Yeap B.Y.
- et al.
Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer.
,5- Śmiech M.
- Leszczyński P.
- Kono H.
- Wardell C.
- Taniguchi H.
Emerging BRAF mutations in cancer progression and their possible effects on transcriptional networks.
This underlying biological diversity is also reflected in different clinical presentations and outcomes where the V600E subgroup, compared with the non-V600E subgroup, tends to be more often detected in females, never smokers, and those with adenocarcinoma with micropapillary features whereas non-V600E is found almost exclusively in smokers.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,4- Dagogo-Jack I.
- Martinez P.
- Yeap B.Y.
- et al.
Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer.
,6- Perrone F.
- Mazzaschi G.
- Minari R.
- et al.
Multicenter observational study on metastatic non-small cell lung cancer harboring BRAF mutations: focus on clinical characteristics and treatment outcome of V600E and non-V600E subgroups.
BRAF is a clinically relevant mutation in NSCLC, where the BRAF-V600E (class I) mutation, characterized by a 500-fold increase in kinase activity which mediates cell proliferation,
5- Śmiech M.
- Leszczyński P.
- Kono H.
- Wardell C.
- Taniguchi H.
Emerging BRAF mutations in cancer progression and their possible effects on transcriptional networks.
comprises approximately half of all
BRAF mutations and can be targeted through dual inhibition of the
BRAF and
MEK pathways.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,7- Tan I.
- Stinchcombe T.E.
- Ready N.E.
- et al.
Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study.
The combination of the
BRAF inhibitor dabrafenib and the
MEK inhibitor trametinib was found to have both safety and efficacy in the clinical trial setting, reporting response rates of 63% and progression-free survival (PFS) of 10.9 months. Dual-targeted
BRAF/
MEK inhibition is currently the recommended first-line treatment for
BRAF-V600E–driven advanced NSCLC in Canada,
8Dabrafenib and trametinib for non-small cell lung cancer BRAF V600 mutation.
although optimal sequencing has not yet been evaluated in prospective studies.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,9- Planchard D.
- Besse B.
- Groen H.J.M.
- et al.
Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis.
Availability of targeted therapies for
BRAF-V600E is important for optimal patient outcome, as lower-than-expected survival times and response to platinum-based chemotherapy regimens have been noted among patients with V600E mutations.
3- Ferrara M.G.
- Di Noia V.
- D’Argento E.
- et al.
Oncogene-addicted non-small-cell lung cancer: treatment opportunities and future perspectives.
,10- Leonetti A.
- Facchinetti F.
- Rossi G.
- et al.
BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall.
Other
BRAF mutations in NSCLC, the non-V600E (classes II and III) mutations, currently lack targeted therapy options, although trials investigating
RAS/
RAF/
MEK inhibition for non-V600E
BRAF are undergoing.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,7- Tan I.
- Stinchcombe T.E.
- Ready N.E.
- et al.
Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study.
Current guidelines recommend that
BRAF non-V600E be managed the same as nononcogene-driven NSCLC, which relies on immune checkpoint inhibitor (ICI) either as a monotherapy (for programmed death-ligand 1 [PD-L1] ≥ 50%) or with concurrent platinum-doublet–based cytotoxic chemotherapy (agnostic to PD-L1 expression) in the absence of contraindications.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
Nevertheless, there is evidence that ICI-based regimens may elicit poor treatment response in oncogene-driven NSCLC,
3- Ferrara M.G.
- Di Noia V.
- D’Argento E.
- et al.
Oncogene-addicted non-small-cell lung cancer: treatment opportunities and future perspectives.
although whether, or to what degree, this is also true for oncogene-driven
BRAF mutation-positive NSCLC remains unresolved, and more studies are required to move toward understanding the role of ICI in
BRAF-mutated NSCLC. Granularity about the activity of current standard-of-care chemoimmunotherapy combinations in
BRAF-mutated contexts is missing from pivotal studies such as KEYNOTE-189 and CheckMate-024.
11- Gandhi L.
- Rodríguez-Abreu D.
- Gadgeel S.
- et al.
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
,12- Reck M.
- Rodríguez-Abreu D.
- Robinson A.G.
- et al.
Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
Some retrospective reviews have revealed limited response and outcome to ICI among patients with
BRAF mutations.
7- Tan I.
- Stinchcombe T.E.
- Ready N.E.
- et al.
Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study.
,13- Dudnik E.
- Bar J.
- Peled N.
- et al.
Efficacy and safety of BRAF inhibitors with or without MEK inhibitors in BRAF-mutant advanced non–small-cell lung cancer: findings from a real-life cohort.
,14- Mazieres J.
- Drilon A.
- Lusque A.
- et al.
Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
Other studies suggest that in
BRAF-mutated NSCLC—particularly among non-V600E subtypes—higher rates of smoking and smoking-associated up-regulation in PD-L1 expression and tumor mutational burden (TMB) may increase sensitivity to ICI and elicit similar response as found in ICI-treated unselected NSCLC populations.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,15- Guisier F.
- Dubos-Arvis C.
- Viñas F.
- et al.
Efficacy and safety of anti–PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01–2018.
,16- Abuali I.
- Lee C.S.
- Seetharamu N.
A narrative review of the management of BRAF non-V600E mutated metastatic non-small cell lung cancer.
Clarity regarding the role of both targeted and ICI-based regimens in BRAF-mutated NSCLC is of importance to management and subsequent outcome for patients with this form of NSCLC. It is also important to recognize that the data which inform the guideline-recommended treatment regimens for BRAF-mutated NSCLC are based on that derived from the clinical trial context where patients may not adequately or accurately represent those encountered in routine, real-world clinical practice. Therefore, an understanding of the characteristics, management, treatment patterns, and response to guideline-recommended therapies for BRAF-mutated NSCLC in real world is increasingly important. To help address these knowledge gaps, this study described the clinical characteristics and treatment patterns of patients with BRAF-mutated NSCLC in the province of Alberta, Canada. In addition, we investigated the outcomes of BRAF-V600E patients treated with dual-targeted BRAF/MEK inhibition and explored the response to ICI-based systemic therapy regimens in both BRAF-V600E and non-V600E cohorts.
Discussion
This retrospective review explored the treatment patterns and outcome of 53 real-world patients with a BRAF mutation, with a focus on the management and prognosis of those 46 patients who experienced advanced disease, where BRAF mutation type becomes an important factor in the available treatment options (targeted versus ICI based) in the palliative setting. This study plays a role in addressing this evidence gap, by not only exploring the real-world effectiveness of dual-targeted BRAF/MEK inhibition for V600E mutation-positive patients but also assessing the clinical effectiveness of ICI-based regimens for both patients with non-V600E mutation-positive NSCLC, as standard of care, and a subset of V600E mutations who accessed ICI-based systemic therapy in lieu of targeted treatments, primarily in the first-line setting.
As a real-world study encompassing all cases of NSCLC with a
BRAF mutation within the southern portion of the Canadian province of Alberta (population approximately 1.5 million),
25- Wu J.S.Y.
- Pinilla J.
- Watson M.
- Verma S.
- Olivotto I.A.
Medical assistance in dying for cancer patients one year after legalization: a collaborative approach at a comprehensive cancer centre.
this study was able to capture the diversity inherent among patients with a
BRAF mutation encountered in routine clinical practice and to reveal the disease management decisions and outcome of a real clinical population. The cohort presented represents a clinically reproducible, real-world population treated in both academic and community centers. The
BRAF mutation-positive patients in this population possessed similar characteristics to other populations with
BRAF-mutated NSCLC described in the literature, namely, those with Caucasian ancestry, a history of smoking, and older age at diagnosis,
10- Leonetti A.
- Facchinetti F.
- Rossi G.
- et al.
BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall.
,26- Ding X.
- Zhang Z.
- Jiang T.
- et al.
Clinicopathologic characteristics and outcomes of Chinese patients with non-small-cell lung cancer and BRAF mutation.
and a slight majority of women, particularly among the V600E subgroup.
10- Leonetti A.
- Facchinetti F.
- Rossi G.
- et al.
BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall.
,27- Auliac J.B.
- Bayle S.
- Do P.
- et al.
Efficacy of dabrafenib plus trametinib combination in patients with BRAF V600E-mutant NSCLC in real-world setting: GFPC 01–2019.
Within its geographic context, we observed a marginally higher rate of palliative-intent systemic therapy uptake among the
BRAF-mutated cohort compared with what has been historically observed within the southern Alberta NSCLC population (61% versus 46%)
28- Ko J.J.
- Tudor R.
- Li H.
- et al.
Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003–2006 with 2010–2011.
and a considerably higher survival time (
Fig. 2B; 34.1 mo) than what was observed among unselected patients with NSCLC receiving cytotoxic chemotherapy in Alberta (11.5 mo).
2- Tabbò F.
- Pisano C.
- Mazieres J.
- et al.
How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC).
,28- Ko J.J.
- Tudor R.
- Li H.
- et al.
Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003–2006 with 2010–2011.
,29- Cardarella S.
- Ogino A.
- Nishino M.
- et al.
Clinical, pathologic, and biologic features associated with BRAF mutations in non–small cell lung cancer.
This suggests increased treatment options for NSCLC in the palliative context as a whole (ICI-based regimens) alongside targeted options for BRAF-V600E mutations which have a positive impact on systemic therapy use and patient prognosis.
Similar to other studies, this study found no significant differences in demographic or clinicopathologic features between those with the V600E and non-V600E mutation, with the exception of differences in smoking history and the rate and type of co-mutated oncodrivers.
6- Perrone F.
- Mazzaschi G.
- Minari R.
- et al.
Multicenter observational study on metastatic non-small cell lung cancer harboring BRAF mutations: focus on clinical characteristics and treatment outcome of V600E and non-V600E subgroups.
,30- Litvak A.M.
- Paik P.K.
- Woo K.M.
- et al.
Clinical characteristics and course of 63 patients with BRAF mutant lung cancers.
Although rates of concurrent oncodriver mutation were similar between V600E and non-V600E mutation-positive cohorts, the non-V600E subgroup had a higher incidence of concurrent
KRAS mutations, whereas concurrent
PIK3CA mutations were more frequently found in association with
V600E mutations. Smoking history seems a distinctive clinical characteristic in
BRAF, both in terms of a higher prevalence of smoking history among
BRAF-mutated populations as a whole compared with several other oncogene-driven forms of NSCLC (
EGFR,
ALK,
ROS1),
6- Perrone F.
- Mazzaschi G.
- Minari R.
- et al.
Multicenter observational study on metastatic non-small cell lung cancer harboring BRAF mutations: focus on clinical characteristics and treatment outcome of V600E and non-V600E subgroups.
,31- Chen D.
- Zhang L.Q.
- Huang J.F.
- et al.
BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis.
and a further distinction where patients with the V600E mutation tend to possess lower smoking rates than non-V600E mutation-positive patients; the rate of nonsmoking among V600E mutation-positive patients in this Alberta study cohort (23%) was analogous to that of both phase 2 and real-world cohorts.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,2- Tabbò F.
- Pisano C.
- Mazieres J.
- et al.
How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC).
,4- Dagogo-Jack I.
- Martinez P.
- Yeap B.Y.
- et al.
Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer.
,9- Planchard D.
- Besse B.
- Groen H.J.M.
- et al.
Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis.
Similarly, this study aligns with other contemporary studies that have found no significant difference in survival between systemically treated V600E and non-V600E mutation-positive cohorts (log-rank
p = 0.9;
Fig. 2C),
6- Perrone F.
- Mazzaschi G.
- Minari R.
- et al.
Multicenter observational study on metastatic non-small cell lung cancer harboring BRAF mutations: focus on clinical characteristics and treatment outcome of V600E and non-V600E subgroups.
,7- Tan I.
- Stinchcombe T.E.
- Ready N.E.
- et al.
Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study.
although it should be noted that there were no studies to serve as comparator to this real-world
BRAF mutation-positive population given that the V600E mutation-positive patients within the Alberta cohort were treated with a mix of ICI-based regimens and dual
BRAF/
MEK inhibition. Reports suggesting poorer outcome among those cohorts possessing a V600E mutation, in comparison to non-V600E mutations, consisted of V600E mutation-positive cohorts primarily treated with cytotoxic chemotherapy,
4- Dagogo-Jack I.
- Martinez P.
- Yeap B.Y.
- et al.
Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer.
,10- Leonetti A.
- Facchinetti F.
- Rossi G.
- et al.
BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall.
suggesting that in the context of targeted and ICI-based treatments, the previously described poorer outcomes associated with a V600E mutation are diminished.
Exposure to dual-targeted
BRAF/
MEK inhibition for V600E mutation-positive patients was observed to produce clinically meaningful disease control in both treatment naive and pretreated V600E mutation-positive patients (DCR: 71%; RW-mPFS: 16 mo, respectively;
Table 2). This metric of clinical response compares favorably with the phase 2 clinical trial exploring the use of dabrafenib/trametinib for V600E mutation-positive NSCLC.
9- Planchard D.
- Besse B.
- Groen H.J.M.
- et al.
Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis.
When compared with the few other real-world V600E mutation-positive cohorts treated with dual
BRAF/
MEK inhibition,
6- Perrone F.
- Mazzaschi G.
- Minari R.
- et al.
Multicenter observational study on metastatic non-small cell lung cancer harboring BRAF mutations: focus on clinical characteristics and treatment outcome of V600E and non-V600E subgroups.
,13- Dudnik E.
- Bar J.
- Peled N.
- et al.
Efficacy and safety of BRAF inhibitors with or without MEK inhibitors in BRAF-mutant advanced non–small-cell lung cancer: findings from a real-life cohort.
,32- Qu J.
- Shen Q.
- Li Y.
- et al.
Clinical characteristics, co-mutations, and treatment outcomes in advanced non-small-cell lung cancer patients with the BRAF-V600E mutation.
the Alberta cohort exhibited a measure of disease control akin to that of a large European real-world retrospective review (mPFS: 17.5 mo).
27- Auliac J.B.
- Bayle S.
- Do P.
- et al.
Efficacy of dabrafenib plus trametinib combination in patients with BRAF V600E-mutant NSCLC in real-world setting: GFPC 01–2019.
Adverse events in conjunction with dual
BRAF/
MEK inhibition within this cohort were experienced by half of the cohort and serious side effects were observed in tandem with progressive disease rending causation of adverse symptoms unclear. This study then adds to the evidence supporting the effectiveness of dual
BRAF/
MEK inhibition for V600E mutations and suggests that this therapeutic combination is equally effective for real-world patients as it is for those treated in the clinical trial setting.
Use of ICI-based regimens was the most frequent first-line palliative treatment for both non-V600E (70%) and V600E (44%) mutation-positive cohorts, reflecting current guidelines which recommend that patients with a
BRAF mutation be offered ICI-based therapies on the basis of PD-L1 expression in the absence of available targeted options.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,26- Ding X.
- Zhang Z.
- Jiang T.
- et al.
Clinicopathologic characteristics and outcomes of Chinese patients with non-small-cell lung cancer and BRAF mutation.
ICI was delivered primarily as pembrolizumab monotherapy among patients with PD-L1 greater than or equal to 50%, reflecting a high rate of PD-L1 up-regulation (69% PD-L1 high) in this study cohort, a phenomenon which has been previously described in another real-world
BRAF mutation-positive cohort (42% PD-L1-high).
33- Dudnik E.
- Peled N.
- Nechushtan H.
- et al.
BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors.
Use of pembrolizumab-based ICI—either as a monotherapy for PD-L1 greater than or equal to 50% or in conjunction with concurrent platinum-based chemotherapy for PD-L1 less than 50%—revealed a measure of disease control (ORR: 38%; RW-mPFS: 10.5 mo;
Table 3) in treatment-naive V600E and non-V600E mutation-positive patients, respectively, which aligns with the outcomes found among clinical trial patients treated with pembrolizumab monotherapy (KEYNOTE-24: ORR = 45%, mPFS = 10.3 mo) and concurrent pembrolizumab plus chemotherapy (KEYNOTE-189: DCR = 47%, mPFS = 8.8 mo).
11- Gandhi L.
- Rodríguez-Abreu D.
- Gadgeel S.
- et al.
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
,12- Reck M.
- Rodríguez-Abreu D.
- Robinson A.G.
- et al.
Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
Similarly, severe adverse events were all immune-related events—colitis, pneumonitis, and severe upper respiratory tract infection, requiring hospitalization and ICI termination—and occurred in 27% of the real-world Alberta study cohort, mirroring the types of adverse events (colitis/pneumonitis) observed in KEYNOTE-24 and -189 cohorts,
11- Gandhi L.
- Rodríguez-Abreu D.
- Gadgeel S.
- et al.
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
,12- Reck M.
- Rodríguez-Abreu D.
- Robinson A.G.
- et al.
Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
and with similar frequency to the KEYNOTE-24 cohort (29%),
12- Reck M.
- Rodríguez-Abreu D.
- Robinson A.G.
- et al.
Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
further supporting the assertion that the outcomes among these real-world
BRAF-mutated patients are well described by and consistent with BRAF unselected clinical trial cohorts.
The Alberta
BRAF-mutation positive cohort treated with ICI-based regimens had a longer time to progression (10 mo versus <5 mo) in comparison to other real-world reviews of similarly treated
BRAF mutation-positive populations.
13- Dudnik E.
- Bar J.
- Peled N.
- et al.
Efficacy and safety of BRAF inhibitors with or without MEK inhibitors in BRAF-mutant advanced non–small-cell lung cancer: findings from a real-life cohort.
, 14- Mazieres J.
- Drilon A.
- Lusque A.
- et al.
Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
, 15- Guisier F.
- Dubos-Arvis C.
- Viñas F.
- et al.
Efficacy and safety of anti–PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01–2018.
Underlying differences among these real-world patient populations, including smoking rates, TMB, or PD-L1 level, could affect response to ICI-based regimens.
2- Tabbò F.
- Pisano C.
- Mazieres J.
- et al.
How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC).
,10- Leonetti A.
- Facchinetti F.
- Rossi G.
- et al.
BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall.
,32- Qu J.
- Shen Q.
- Li Y.
- et al.
Clinical characteristics, co-mutations, and treatment outcomes in advanced non-small-cell lung cancer patients with the BRAF-V600E mutation.
Although TMB was not assessed in the context of this study, smoking is a known correlate of both increased TMB through the promotion of somatic mutations
34- Sun L.Y.
- Cen W.J.
- Tang W.T.
- et al.
Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer.
,35- Kim J.
- Ha H.
- Park J.
- Cho J.
- Lim J.H.
- Lee M.H.
Association of smoking status with efficacy of first-line immune checkpoint inhibitors in advanced non-small cell lung cancers: a systematic review and meta-analysis.
and up-regulated PD-L1,
36- Zaleskis G.
- Pasukoniene V.
- Characiejus D.
- Urbonas V.
Do the benefits of being a smoker hint at the existence of PD-1/PD-L1 sensitizers for patients on single-agent immunotherapy?.
all of which are associated with improved response to ICI-based therapy. This study cohort consisted predominantly of individuals with a history of smoking and did have high levels of PD-L1 positivity (93% PD-L1 > 1%; 73% PD-L1 ≥ 50%) which could account for the evident benefit of ICI-based regimens in this study cohort. Unique to this study was the ability to compare the responses of ICI-based or targeted therapy in the first-line palliative setting for V600E mutation-positive patients. The dual-targeted
BRAF/MEK inhibition and ICI-based regimens produced similar clinical response ([DCR: 71%, 60%] and duration of disease control [median PFS, 16.0 and 10.4 mo], respectively) and suggest that both targeted and nontargeted systemic therapy can provide meaningful benefit to V600E mutation-positive patients. Furthermore, survival outcomes do not differ significantly, regardless of category of
BRAF mutation (V600E or non-V600E) nor type of systemic therapy received (log-rank
p = 0.2;
Fig. 2D), although small numbers at risk may decrease the power of statistical detection of differences. Unfortunately, 2L therapy rates among the Alberta patients with a
BRAF mutation and treated with dual-targeted
BRAF/
MEK inhibition or ICI-based regimens in the first-line setting were low (19%), precluding the opportunity to review the outcomes and safety of sequential use of targeted and nontargeted systemic therapies for V600E mutations, to independently assess the impact of systemic therapy type on outcome, or to add statistically supported evidence to the question of optimal sequencing of
BRAF/MEK inhibitors and ICI-based systemic therapies in
BRAF mutation-positive lung cancer. As found in the DREAMseq Trial for V600E mutation-positive melanoma, treatment sequence in the context of multiple lines of systemic therapy has the ability to affect outcome,
37- Atkins M.B.
- Lee S.J.
- Chmielowski B.
- et al.
DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): a phase III trial—ECOG-ACRIN EA6134.
but it may also pose challenges associated with toxicity, particularly in the context of use of tyrosine kinase inhibitors after ICI-based therapies.
38- Adderley H.
- Blackhall F.H.
- Lindsay C.R.
Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer.
Included within the Alberta cohort was a single patient receiving dual
BRAF/MEK inhibition after exposure to ICI. In this instance, evidence of clinical benefit (partial response, duration of therapy > 18 mo) was observed in the context of minimal side effects managed through a brief treatment break (grade 2 fatigue). Although a reassuring account, the need for clarity regarding treatment sequence and the balance between treatment effectiveness and safety is of upmost importance for V600E mutation-positive NSCLC in light of the apparent benefit of both ICI-based and tyrosine kinase–inhibiting systemic therapies. Low uptake of second-line therapy—either owing to a lack of suitable options or patient performance status precluding further systemic therapy—likely represents an obstacle to improving outcome for patients with a
BRAF mutation where incremental additions to disease control facilitated through multiple lines of systemic therapy can contribute to improved outcomes.
This study adds some interesting data to the discussion regarding both the existence and incidence of other concurrent oncodrivers in addition to a
BRAF mutation. Previously believed to be mutually exclusive to other known oncodrivers such as
KRAS,
EGFR, and
ALK,
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
,39- Bourhis A.
- Remoué A.
- Uguen A.
KRAS and BRAF double mutations and functional classes of BRAF mutations in non–small-cell lung cancers.
more contemporary studies, including this review of Alberta patients with
BRAF mutation, suggest that co-mutation of
BRAF and
EGFR,
KRAS, or
PIK3CA occurs with some frequency, recorded at 25% in this study and identified in 14% to 16% of other reviews, depending on type of co-mutation investigated.
26- Ding X.
- Zhang Z.
- Jiang T.
- et al.
Clinicopathologic characteristics and outcomes of Chinese patients with non-small-cell lung cancer and BRAF mutation.
,32- Qu J.
- Shen Q.
- Li Y.
- et al.
Clinical characteristics, co-mutations, and treatment outcomes in advanced non-small-cell lung cancer patients with the BRAF-V600E mutation.
,40- Villaruz L.C.
- Socinski M.A.
- Abberbock S.
- et al.
Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium.
We excluded from the analysis two co-occurring
EGFR-mutated patients owing to different treatment options available in the context of a canonical
EGFR mutation, but we made a decision to retain dual
BRAF-KRAS and
BRAF-PIK3CA mutation-positive patients within our cohort. Within the context of this study time period, the presence of a co-mutated
KRAS or
PIK3CA gene has no impact on treatment options in the first-line setting and thus reflects the real-world management of patients with these co-mutations. Within the remaining study cohort, co-occurring
BRAF and
KRAS mutations were most common and more frequently found in association with the non-V600E mutation-positive subgroup, which has also been observed in other studies.
4- Dagogo-Jack I.
- Martinez P.
- Yeap B.Y.
- et al.
Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer.
BRAF detection for the patients in this study was performed using multiplex assays ensuring the simultaneous detection of
BRAF,
EGFR,
KRAS,
PIK3CA, and
ERBB2 mutations if present; increased use of multiplex testing panels and next-generation sequencing techniques to detect genetic alterations in NSCLC will likely serve to increase the rate at which co-mutations are detected. The presence of other oncodrivers in conjunction with
BRAF is clinically significant, as it creates both possibilities and challenges: the possibility of using co-inhibition of BRAF and other oncogenic pathways either in tandem or sequentially and the possibility of co-mutations (i.e.,
KRAS and
PIK3CA) encouraging up-regulation of PD-L1 and subsequent benefit of ICI-based regimens
41- Quan Z.
- Yang Y.
- Zheng H.
- et al.
Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer.
,42- Falk A.T.
- Yazbeck N.
- Guibert N.
- et al.
Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients.
; the challenge of co-occurring mutations (specifically
KRAS) being a mechanism of primary resistance to dual
BRAF/MEK inhibition.
32- Qu J.
- Shen Q.
- Li Y.
- et al.
Clinical characteristics, co-mutations, and treatment outcomes in advanced non-small-cell lung cancer patients with the BRAF-V600E mutation.
Indeed, in this study, we observed both primary resistance to dabrafenib/trametinib in the context of a dual
BRAF-KRAS mutation, including a rate of primary resistance double that found within the phase 2 clinical trial of dabrafenib/trametinib (33% versus 14%), which did not include dual
BRAF-KRAS mutations.
9- Planchard D.
- Besse B.
- Groen H.J.M.
- et al.
Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis.
Conversely, although the rate of intrinsic
BRAF mutations is relatively low,
BRAF mutations may also be acquired, thereby representing one mechanism of resistance to EGFR-inhibiting–targeted therapies. BRAF V600E mutations have been identified in 3% to 10% of patients in the AURA3 and FLAURA clinical trials who exhibited resistance to the third-generation EGFR inhibitor osimertinib.
1- Frisone D.
- Friedlaender A.
- Malapelle U.
- Banna G.
- Addeo A.
A BRAF new world.
Effective management of
BRAF-mutated NSCLC is then poised to play an important role in the successful management of oncogene-addicted NSCLC.
There are some limitations to this study: as a retrospective, real-world review, there is a lack of consistency in standardized response assessment because toxicity reporting and patients have variable follow-up schedules. Detailed information regarding BRAF functional class, tumor grade, or adenocarcinoma histology patterns was not available for this cohort. In addition, the small size of this cohort and consequent limitations to robust statistical analysis are acknowledged owing to the relative rarity of BRAF mutations and presence of co-mutations, so the results should be interpreted cautiously and within this context. To this end, small sample size and proportions of censored end points may have affected statistical significance of univariate measures of outcome and prohibited the use of multivariate Cox regression analysis to assess prognostic factors associated with treatment response or outcome. Low 2L therapy uptake rates render this study unable to add to the literature regarding optimal treatment sequence in the context of targeted and ICI-based treatment options. Despite such limitations, this study does have some distinct strengths: First, as a population-based study, it represents all patients with a BRAF mutation within southern Alberta (regional population of approximately 1.5 million). Second, Alberta possesses a single-payer universal health care model that lends equality to care and treatment, irrespective of financial situation or insurance provider, and eliminates potential cohort identification biases. Finally, inclusive and comprehensive real-world data sets are rare, particularly within the North American context, but they are imperative to understand the effectiveness of treatment options for rare molecular subgroups and to determine the experience and outcomes of patients who would not meet clinical trial inclusion criteria.
In summary, to our knowledge, this represents the first single-payer, population-based review of patients with BRAF mutations in North America. The results of this study complement the findings of both clinical trials and other real-world reviews in confirming the safety and value of dual BRAF/MEK inhibition for a V600E mutation. Importantly, this study was able to reveal the effectiveness of ICI-based regimens in both non-V600E and V600E mutation-positive real-world patients where ICI-based regimens elicited similar clinical response and duration of disease control, irrespective of BRAF mutation type, to ICI-treated, BRAF-unselected clinical trial cohorts. In addition, of note, this study was able to find a high level of concurrent mutation; the impact of double BRAF-KRAS or BRAF-PIK3CA mutations on TMB and PD-L1 expression has known implications for ICI response and should be a focus of future investigation to lend clarity to use of ICI for BRAF mutations, including the role of ICI-based regimens after targeted BRAF/MEK inhibition.