Novel Triplets May Overcome Resistance to Targeted Therapy in BRAF+ Melanoma

Grant McArthur, MBBS, PhD

The addition of anti–PD-1/PD-L1 to combination BRAF and MEK inhibition has been shown to improve progression-free survival (PFS) and duration of response (DOR) in patients with BRAF-mutated melanoma, suggesting potential to overcome resistance to targeted approaches, said Grant McArthur, MBBS, PhD, in a presentation during the 2020 SMR Virtual Congress.¹

Targeted therapies, such as BRAF and MEK inhibitors, offer an advantage of rapid and high response rates in patients with advanced melanoma harboring a BRAF mutation. However, the limitation of this approach is the development of resistance, according to McArthur. Most of the patients who receive BRAF/MEK inhibition in this setting will experience disease progression. 

“If we were able to overcome resistance to targeted therapies, this would be a major benefit for patients,” noted McArthur, who is executive director of the Victorian Comprehensive Cancer Centre, inaugural Lorenzo Galli Chair of Melanoma and Skin Cancers at the University of Melbourne, Australia, and a senior principal research fellow.

Several approaches have been explored in an attempt to overcome resistance to targeted treatment approaches, such as targeting acquired mechanisms of resistance, the development of novel BRAF inhibitors, overcoming early drug adaptation or tolerance, and the enhancement of antitumor immunity.

“[It has been shown] that the combination of BRAF and MEK inhibition could induce an influx of CD8 and CD4 T cells in the tumor and generate a favorable tumor microenvironment with a reduction in T-reg and myeloid-derived suppressor cells,” said McArthur. “This has led to the hypothesis that it might be possible to overcome resistance to targeted therapies by enhancing this immune response in the tumor through the addition of immune checkpoint inhibitors.”

In his presentation, McArthur walked the virtual audience through 3 pivotal trials that further evaluated this hypothesis: the phase 2 KEYNOTE-022 trial (NCT02130466), the phase 3 IMspire150 trial (NCT02908672), and the phase 3 COMBI-i trial (NCT02967692).

KEYNOTE-022

The phase 2 KEYNOTE-022 trial² enrolled a total of 120 patients with histologically confirmed unresectable or metastatic stage IV BRAF V600E/K–mutated melanoma. Patients had to be treatment naïve, have measurable disease, and an ECOG performance status of either 0 or 1 to be eligible. Participants were stratified based on performance status (0 vs 1) and

lactic acid dehydrogenase (LDH) level (greater than 1.1 x upper limit of normal [ULN] vs 1.1 or less x ULN).

In the trial, patients were randomized 1:1 to receive either pembrolizumab (Keytruda) at 2 mg/kg once every 3 weeks plus dabrafenib (Tafinlar) at 150 mg twice daily and trametinib (Mekinist) at 2 mg once daily for up to 2 years (n = 60) or placebo with the same dose and schedule of dabrafenib/trametinib (n = 60). The primary end point of the trial was PFS.

Results showed that the median PFS in the triplet arm was 16.9 months (95% CI, 11.3-27.9) versus 10.7 months (95% CI, 7.2-16.8) with the targeted therapy alone (HR, 0.53; 95% CI, 0.34-0.83). The 12-month PFS rates in the investigational and control arms were 62% and 47%, respectively; at 24 months, these rates were 41% and 16%, respectively.

The benefit was found to extend to all subsets of patients examined, irrespective of age, sex, ECOG performance status, LDH, and PD-L1 expression.

“If the triplet combination was overcoming resistance to the targeted therapy one would anticipate an improved DOR and this was, indeed, seen in the KEYNOTE-022 trial,” noted McArthur. The median DOR with the triplet regimen was 25.1 months (95% CI, 14.1–not reached) versus 12.1 months with the doublet (95% CI, 6.0-15.7; HR, 0.32; 95% CI, 0.17-0.59). The 24-month DOR rates with the triplet and doublet regimens were 55% and 16%, respectively.

The overall survival (OS) data remain immature but a trend to improved survival favoring the triplet arm was observed (HR, 0.64; 95% CI, 0.38-1.06). The 24-month OS rate was 63% with the triplet versus 52% with the doublet.

“One useful parameter to look at how tolerable a treatment is, is the rate of treatment discontinuation,” said McArthur. “This was, in fact, higher in the triplet arm compared with the combination targeted therapy arm, with 30% of patients discontinuing versus approximately 17%, respectively.”

Key treatment-related adverse effects (TRAEs) that occurred in 15% or more patients in either treatment arm included rash, arthralgia, and diarrhea—all known toxicities associated with anti–PD-1 treatment, said McArthur.

IMspire150

Patients with previously untreated, advanced, BRAF V600–mutated melanoma with an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 criteria were enrolled to the phase 3 IMspire150 trial.³ In this trial, patients were stratified by geographic region along with centrally evaluated LDH level.

Here, participants were randomized 1:1 to receive either a triplet regimen comprised of atezolizumab (Tecentriq) at 840 mg on days 1 and 15 plus vemurafenib (Zelboraf) at 720 mg twice daily and cobimetinib (Cotellic) at 60 mg once daily on days 1 to 21 or placebo with vemurafenib/cobimetinib administered at the same dosing and schedule.

“This study had an important difference to the KEYNOTE-022 trial in that there was a 28-day lead-in with targeted therapy alone before the anti–PD-L1 drug was added,” noted McArthur.

The primary end point of the trial was PFS per investigator assessment, while key secondary end points included PFS per independent review committee, objective response, DOR, and OS.

This trial also met its primary end point, showing an improvement in investigator-assessed PFS that favored the triplet regimen. The median PFS was 15.1 months (95% CI, 11.4-18.4) with the triplet versus 10.6 months (95% CI, 9.3-12.7) with the doublet (log-rank P = .0249). The PFS rates at 6 months in the investigational and control arms were 72.8% versus 74.2%, respectively; the 12-month PFS rates were 54.0% versus 45.1%, respectively, while the 18-month PFS rates were 43.6% versus 31.6%, respectively. Again, all subsets of patients who were analyzed achieved benefit with the triplet.

The addition of atezolizumab to the targeted therapy combination was also found to prolong DOR compared with the doublet regimen, at 21.0 months (95% CI, 15.1–not evaluable [NE]) versus 12.6 months (95% CI, 10.5-16.6), respectively. The DORs at 12 months in the investigational and control arms were 69.4% versus 50.8%, respectively.

Moreover, although the OS data are still immature, the OS favored the triplet arm. The median OS in the atezolizumab arm was 28.8 months (95% CI, 27.4-NE) versus 25.1 months (95% CI, 22.3-NE) in the control arm. The 12-month OS rate in the triplet arm was 76.1% versus 76.7% in the doublet arm; these rates were 60.4% and 53.1%, respectively, at 24 months.

Regarding safety, the most prominent toxicities observed were pyrexia and arthralgia, which were more commonly reported on the triplet arm, as were abnormalities in liver function tests and thyroid dysfunction, according to McArthur.

“There was a similar rate of discontinuation, however, between the 2 arms, possibly related to the fact that there was the 1 cycle lead-in without the anti–PD-L1 therapy,” added McArthur.

COMBI-i

The phase 3 COMBI-i trial⁴ enrolled a total of 532 treatment-naïve patients with BRAF V600–mutated unresectable or metastatic melanoma who did not have active brain metastases and had an ECOG performance status of 2 or less. Participants were stratified by performance status and LDH level and they were randomized to either spartalizumab at 400 mg every 4 weeks plus dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily or placebo with dabrafenib/trametinib given at the same dose and schedule.

The primary end point of the trial was investigator-assessed PFS in accordance with RECIST v1.1 criteria, while secondary end points included OS, objective response rate, DOR, disease control rate, safety, patient-reported outcomes, and pharmacokinetics.

“In this study, we saw a trend toward improvement in PFS in the triplet-therapy arm, but it did not reach statistical significance,” said McArthur. “However, there was an approximately similar magnitude of benefit seen with this triplet therapy versus the doublet therapy similar to KEYNOTE-022 and IMspire150.”

The median PFS in the spartalizumab arm was 16.2 months (95% CI, 12.7-23.9) versus 12.0 months (95% CI, 10.2-15.4) in the doublet arm (HR, 0.82; 95% CI, 0.655-1.027; 1-sided P =.042). The PFS rates in the investigational and control arms at 12 months were 58% versus 50%, respectively; at 24 months, these rates were 44% versus 36%, respectively. 

The triplet was beneficial in all subsets analyzed. “Notably, patients with multiple sites of metastatic disease of 3 or more or patients with high disease burden as measured by the sum of lesions diameters at baseline achieved significant benefit from the triplet therapy; that may potentially identify a subset that may get greater benefit from this approach,” said McArthur.

A trend toward OS favoring the triplet therapy was observed in this trial, as well, although the median OS had not been reached in either arm (HR, 0.785; 95% CI, 0.589-1.047). The OS rate at 12 months with the spartalizumab combination was 84% versus 79% with the doublet; the 24-month OS rates were 68% versus 62%, respectively.

With regard to safety, patients in the spartalizumab arm experienced more AEs that led to treatment discontinuation than those in the doublet arm. Specifically, 15.7% of patients in the triplet arm experienced all-grade AEs that resulted in discontinued treatment versus 9.1% of those in the doublet arm; 12.4% and 8.0%, respectively, were related to treatment. The toxicities reported were in line with what had previously been reported with these agents, including diarrhea, pyrexia, and abnormalities in liver function tests.

“The COMBI-i study looked at subsets of patients with high tumor mutational burden (TMB) and showed a relatively greater benefit in patients with high TMB,” added McArthur. “[Additional results showed] that patients who had an inflamed tumor microenvironment had higher PFS versus those who did not.”

Future Directions

Although combining immune checkpoint inhibition with targeted therapy has shown promise in potentially overcoming resistance to targeted therapy in this patient population, further follow-up is needed to understand the impact of these combinations on OS, said McArthur.

“However, I do point out to you that when one looks at the PFS curves, there's no sign yet of a plateau,” McArthur emphasized. “If this approach was a robust mechanism to overcome resistance, then one would anticipate a plateau in the PFS curves. Ongoing follow up with regard to this will be important.”

References

1. McArthur G. Overcoming resistance to targeted therapy. Presented at: 2020 SMR Virtual Congress; October 28, 2020; Virtual.
2. Ferucci P, Ascierto PA, Maio M. Updated survival in patients (pts) with BRAF-mutant melanoma administered pembrolizumab (pembro), dabrafenib (D), and trametinib (T). Presented at: 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
3. McArthur GA, Stroyakovskiy D, Gogas H, et al. CT012 — Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: primary results from the phase 3 IMspire150 trial. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.
4. Nathan P, Dummer R, Long GV, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: results from the randomized part 3 of the phase 3 COMBI-i trial. Ann Oncol. 2020;31(suppl 4):S1172. doi:10.1016/j.annonc.2020.08.2273