Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Evolving Paradigms, BRAF-Mutant Melanoma,

With the development of novel targeted and immunotherapeutic agents that are more efficacious than traditional chemotherapy, treatment paradigms in melanoma have undergone major changes.

BRAFmutation status, tumor growth rate, and the presence or absence of cancer-related symptoms.

Immunotherapies with agents that block CTLA-4 or PD-1/PD-L1 checkpoints have been associated with durable responses in a subset of patients, and are often considered for patients with low-volume, asymptomatic metastatic melanoma. Targeted therapies, on the other side, are preferred for patients withBRAF-mutant tumors who have symptomatic disease and benefit from the rapid response associated with these agents.1

A main concern with targeted therapies is tumor resistance that ultimately develops in most patients within 6-12 months. However, as Jason J. Luke, MD, with the University of Chicago Medicine states, “A sizable fraction of patients do very, very well for a long time on targeted therapy.”

A long-term analysis has shown that approximately one fifth of patients withBRAFV600-mutant melanoma receiving combined dabrafenib/trametinib remained progression-free after 3 years, suggesting a plateau of the survival curve.2

According to lead author Georgina Long, MD, with the Melanoma Institute Sydney, Australia, and co-authors,2this defines, “a need to understand the characteristics of patients who derive the greatest benefit from each mode of therapy.” Specifically, “future selection of patients for combined BRAF and MEK inhibition, and the rational design of clinical trials for those who fail it, may be assisted by an analysis of the clinicopathological features of those experiencing long-term benefit and those who progress.”

In their study, Long and colleagues found that good prognostic features such as normal lactate dehydrogenase (LDH) levels, earlier-stage melanoma, and fewer metastatic sites were consistently associated with durable response and prolonged overall survival (OS) with BRAF/MEK inhibitor therapy.2Patients who survived longest on treatment included those with a complete response (CR), according to RECIST, and patients with a normal baseline LDH (63% and 62%, respectively). Data were from 2 cohorts of BRAF-inhibitor naïve patients (n = 78) who had been treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily).2

Similarly, a study evaluating long-term outcomes of patients who received either BRAF or combined BRAF and MEK inhibitor regimens in phase I to III trials with single agent dabrafenib or vemurafenib, or combined dabrafenib/trametinib found that female sex and normal pretreatment LDH levels were the only factors associated with longer progression-free survival (PFS) and OS.3

Lactate Dehydrogenase Serum Level

LDH below the upper limit of normal (ULN) was significantly associated with prolonged survival of patients receiving BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib.2 Patients with a normal LDH at baseline had a median OS of 45.5 months (95% CI, 45.5 to not reached) compared with 16.6 months (95% CI, 11.1-22.6) for patients with an elevated LDH.2 Overall survival rates of patients with normal versus elevated LDH levels at baseline, respectively, were 88% versus 68% at 1 year, 75% versus 18% at 2 years, and 62% versus 5% at 3 years.2

Recent data from phase III COMBI-v trial have also linked baseline LDH serum levels to survival benefits with the dabrafenib/trametinib combination.4According to lead author Caroline Robert, MD, of Institut Gustave Roussy in Paris, “The longest benefit was in patients with an LDH less than or equal to the upper limit of normal, who had a 2-year overall survival rate of 66% and a median progression-free survival of 17.5 months.”

In this patient group, median OS was not yet reached with dabrafenib/trametinib and was 21.5 months with vemurafenib (HR, 0.56), translating to a 44% OS benefit with the combination. Patients with an LDH above the ULN had less benefit with a median OS of 10.6 months with the combination and 8.9 months with vemurafenib monotherapy (HR, 0.81).4

Similar observations are emerging from the phase III evaluation of cobimetinib/vemurafenib. OS benefits of the combination were observed in all patient subgroups.5For patients with both LDH baseline levels, median OS was not reached with the combination and was 23.3 months with vemurafenib. Patients with elevated LDH levels had an OS of 14.8 months with the combination and 11.2 months with vemurafenib alone. According to lead author Victoria Atkinson, MD, of the Princess Alexandra Hospital in Queensland, Australia, “This is consistent with previous combination studies showing that patients with poor prognostic factors do worse.”5

Longer-term analyses of patients who had received both BRAF monotherapy and combined BRAF/MEK therapy have also reported a significant association of normal LDH levels with prolonged survival. Patients with normal LDH levels had a median OS of 23.5 months compared with 7.3 months in patients with elevated LDH levels.3

Across all studies, normal serum LDH levels correlated with continued long-term response without progression (per Cox proportional hazards regression analysis;P= .024,2 or per univariate and multivariate analyses).3In COMBI-v, in patients with low LDH levels, median PFS was 17.5 and 9.2 months with the combination and monotherapy, respectively (HR, 0.55) and 5.5 versus 4.0 months in patients with elevated LDH levels (HR, 0.70).4

According to Alexander Menzies, MBBS, with the Melanoma Institute Sydney, Australia, and co-authors,3 this evidence “suggests that LDH is not simply prognostic. The biology of metastatic tumors that produce different levels of LDH may be distinct; for example, it has been shown that a high serum LDH level reflects an anaerobic oxidative metabolic state. As such, the best treatments for metastatic patients with normal and elevated LDH levels may be different.”

According to Robert, patients with “low LDH respond extremely well to targeted treatment. Patients with high LDH, whatever treatment we use, remain a big medical need. They derive a small benefit each time we evaluate a new, effective therapy. The benefit is always less in this population.”

Tumor Burden and Timing of BRAF MEK Inhibitor Therapy

Consistent features associated with better outcomes with combined BRAF/MEK inhibitor in long-term analyses also included earlier-stage melanoma and fewer metastatic sites. Furthermore, according to Long and co-authors, “good prognostic features at progression seemed to prolong survival from the time of progression but were also associated with receiving subsequent systemic therapy.”2

TABLE 1. Survival by Baseline Characteristics With Dabrafenib/Trametinib

Median OS, months

LDH > ULN

16.6

LDH ≤ ULN

45.5

≥3 disease sites

17.5

<3 disease sites

45.5

Male

23.8

Female

25.5

IIIC/M1a/M1b

not reached

M1c

21.9

&ge;65 years

21.3

<65 years

28.4

Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal.

The presence of less than 3 organ disease sites was a baseline feature that met stringent criteria for association with longer OS (Cox proportional hazard regression analysis).2The median OS in patients with less than 3 metastatic sites was 45.5 versus 17.5 months in patients with ≥3 metastatic sites (HR, 0.36; 95% CI, 0.18-0.69).2The corresponding OS rates were 92% versus 68% at 1 year, 73% versus 30% at 2 years, and 58% versus 19% at 3 years.2In patients with earlier stage disease (IIIC/M1a/M1b vs M1c), the median OS had not been reached and was 21.9 months in patients with M1c stage disease (HR, 0.36; 95% CI, 0.18-0.72). Other baseline features evaluated, including age, sex, ECOG performance status, and prior immunotherapy, did not correlate with added benefit from combination therapy(TABLE 1).2

TABLE 2. Survival Comparison by Baseline Characteristics With Dabrafenib/Trametinib

LDH

≤ ULN vs > ULN

HR, 0.21 (95% CI, 0.10-0.44)

Disease sites

<3 vs ≥3

HR, 0.34 (95% CI, 0.17-0.70)

Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal.

Several indicators of a good prognosis, including the presence of fewer than three metastatic organ sites, lower median sum of diameters, lower melanoma stage, lower ECOG performance status, and no history of brain metastases were baseline factors that were also more frequent among patients who had a continued long-term response without progression.2Consistent with these observations, patients who progressed and did not receive further systemic chemotherapy had higher ECOG performance status, higher LDH, larger sum of diameters of RECIST target lesions at progression, greater absolute change in the RECIST sum of diameters from nadir, progression in the brain, and female sex(TABLE 2).2

Findings that low tumor burden predicts superior long-term outcomes imply that BRAF/MEK inhibitor therapy should also be considered earlier in the disease course, in healthier patients with lower disease burden, in whom immunotherapy is often preferred. Long and co-authors noted that, “on the basis of longer-term survival data from the current study and other studies, it would not be possible to use baseline features to select one therapy over another. Specifically, this study showed that long-term survival and durable responses with dabrafenib plus trametinib are associated with good prognostic features at baseline, including factors associated with low-volume disease—classically considered a hallmark for frontline immunotherapy.”

Observations from a phase Ib trial have also identified tumor burden as a predictor of clinical outcome with BRAF/MEK inhibition with vemurafenib and cobimetinib.6

This study involved 35 BRAF inhibitor-naïve patients withBRAFV600-mutant melanoma and found that early and progressive metabolic response of tumors to dual inhibitor therapy was associated with improved OS. Lead author Grant A. McArthur, MBBS, PhD, with the Peter MacCallum Cancer Centre, Melbourne, Australia, and colleagues evaluated several 18-F-fluorodeoxyglucose (FDG) uptake measures on positron emission tomography (PET) as indicators of tumor burden and glycolytic metabolism in tumors.6

Patients with low values of tumor burden measures at baseline compared with the median (percentage injected dose <0.36% or metabolic tumor volume < 47.5 ml) had a longer OS than patients with tumor burden measures above the median (HR, 0.19,P<.02; HR, 0.14,P= .03).6

The ORR to treatment was 87% by RECIST and median PFS was 13.7 months. Complete metabolic responses (CMR) were obtained by 51% of patients during the second treatment cycle, and patients achieving CMR during the first treatment cycle (14%) had a longer PFS than patients achieving a partial MR (>30% decrease in standard maximum uptake volume; 86%). Tumor burden at baseline was not correlated with metabolic response.6

The authors concluded that, “Marked, early and progressive metabolic response on FDG-PET [was] consistent with successful inhibition of ERK-signaling.”6According to lead author McArthur, these findings fit in with hypotheses that suggest that, “Enhanced inhibition of the RAF/MEK/ERK pathway may lead to more cell death or even a change in tumor microenvironment that is less compatible with long-term cell survival or the reacquisition of a proliferative state […] and that more effective or complete inhibition of RAF/MEK/ERK signaling may indeed produce biological responses that improve overall survival.”7

On-Treatment Features and Biomarkers of Response

Both degree of response and response category have been linked with benefit for targeted therapies. Patients with a complete response (CR; per RECIST) to the combination of dabrafenib/trametinib had numerically higher OS rates than patients with partial response (PR) or stable disease (SD). OS rates at 1, 2, and 3 years were 100%, 88%, and 63% for patients with CR versus 79%, 48%, and 33% for patients with PR, and 69%, 35%, and 35% for patients with SD.2

Among patients receiving either BRAF inhibitor monotherapy or BRAF/MEK inhibitor combination regimens, the RECIST response correlated with PFS and OS (bothP<.001) as a continuous variable, and patients with CR had longer PFS and OS.3According to the authors of this study, the association of potential biomarkers that may associate with response and clinical outcome is complex, because “Mixed responses to treatment often occur with BRAF inhibitors, in which some metastases shrink while others remain stable or grow. Such responses are probably a consequence of molecular heterogeneity, which further affects clinical outcome and confounds biomarker studies.”

Candidate biomarkers of response identified in small studies include markers of MAPK pathway activation and TORC1 activity early during treatment, PTEN status, cell cycle gene aberrations (CCND1 and CDKN2A copy number), and stromal growth factor expression.3

Recent findings from the phase III coBRIM trial of vemurafenib/cobimetinib versus vemurafenib indicate that the presence of co-existing oncogenic mutations in addition toBRAFV600 does not impact response to combination treatment.8Alterations inHRAS, KRAS, NRAS, non-V600BRAF, or receptor tyrosine kinases (RAS/RAF/RTK) were detected in 11% (n = 46) of the study population, and resulted in higher levels of ERK and MEK activation in tumors as detected by protein analysis. However, no correlation with PFS or ORR was identified.8

The analysis of biomarkers that may correlate with response to treatment and treatment toxicity is the focus of an ongoing randomized phase III study (ClinicalTrials.gov identifier NCT02314143). The 3-arm study has been designed to assess sequential effects of BRAF and MEK inhibition on skin, blood and tumor biomarkers, and will compare continuous dabrafenib/trametinib combination therapy with upfront monotherapy with dabrafenib or trametinib followed by combination therapy.

References

  1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines&reg;): Melanoma.NCCNorg.2016; Version 2.2016.
  2. Long GV, Weber JS, Infante JR, et al. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib.J Clin Oncol.2016;34:871-878.
  3. Menzies AM, Wilmott JS, Drummond M, et al. Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.Cancer.2015;121:3826-3835.
  4. Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria Abstract 3301.
  5. Atkinson V, Larkin J, McArthur GA, et al. Improved overall survival with cobimetinib (COBI) and vemurafenib (VEM) in advanced BRAFV600-mutated melanoma and biomarker correlates of efficacy. Presented at: 12th International Congress of the Society for Melanoma Research in San Francisco, California, 21 November 2015.
  6. McArthur GA, Callahan J, Ribas A, et al. Metabolic tumor burden for prediction of overall survival following combined BRAF/MEK inhibition in patients with advanced BRAF mutant melanoma.J Clin Oncol.2014;32:5s:(suppl; abstr 9006).
  7. McArthur GA. Combination Therapies to Inhibit the RAF/MEK/ERK Pathway in Melanoma: We are not Done Yet.Front Oncol.2015;5:161.
  8. Larkin J, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma.J Clin Oncol.2015;33:(suppl; abstr 9006).