Atezolizumab Plus Vemurafenib/Cobimetinib Produces Intracranial Activity in BRAF V600–Mutant Melanoma With CNS Metastases

The addition of atezolizumab (Tecentriq) to vemurafenib (Zelboraf) and cobimetinib (Cotellic) produced promising intracranial activity in patients with BRAF V600–mutated advanced melanoma and central nervous system (CNS) metastases, according to data from the phase 2 TRICOTEL trial (NCT03625141) published in The Lancet.¹

At a median follow-up of 9.7 months (interquartile range [IQR], 6.3-15.0), patients in the BRAF V600 mutation–positive cohort (n = 65) achieved an intracranial objective response rate (ORR) of 42% (95% CI, 29%-54%) per independent review committee (IRC) assessment. Of these responders, 6% experienced a complete response (CR), 35% had a partial response (PR), 28% had stable disease, 5% had a non-CR or progressive disease, 20% experienced progressive disease, 2% were not evaluable, and 5% were missing. The disease control rate at 16 weeks was 38% (95% CI, 27%-61%), and the median intracranial duration of response (DOR) was 7.4 months (95% CI, 5.7-11.0).

At a median follow-up of 6.2 months (IQR, 3.5-23.0), patients in the BRAF V600 wild-type cohort (n = 15) who were treated with atezolizumab plus cobimetinib experienced an intracranial ORR of 27% (95% CI, 8%-55%) per investigator assessment.

“Safety and activity data from the TRICOTEL study suggest a positive risk-benefit ratio for atezolizumab in combination with vemurafenib and cobimetinib in BRAF V600 mutation–positive melanoma with CNS metastases,” wrote Reinhard Drummer, MD, who is the vice director of the Department of Dermatology, director of the CCCZ Clinical Trials Comprehensive Cancer Center Zurich, head of Skin Tumour Centre, and chair of the Expert Group on Immunoncology at University Hospital of Zurich in Switzerland, and colleagues. “To our knowledge, this is the first report of intracranial activity with combined immunotherapy and targeted therapy in patients who were receiving corticosteroids, had symptomatic CNS metastases, or both.”

Although targeted therapeutic approaches have demonstrated intracranial activity in patients with BRAFV600E–positive melanoma, and checkpoint inhibition has demonstrated intracranial efficacy in those with melanoma and CNS metastases, an unmet need remains. Corticosteroids are necessary for the control of neurological symptoms in patients with advanced CNS metastases; however, the immunosuppressive effects of these agents could compromise the activity of immune checkpoint inhibitors.2

Prior data from the phase 3 IMspire150 trial (NCT02908672) showed that the combination of atezolizumab, vemurafenib, and cobimetinib improved progression-free survival (PFS) vs vemurafenib and cobimetinib plus placebo in patients with BRAF V600–mutated advanced melanoma without CNS metastases, and an exploratory analysis of the trial suggested that the triplet delayed the time to first CNS metastases and reduced cumulative incidence of CNS metastases.3

The multicenter, open-label, single-arm TRICOTEL study aimed to further evaluate the triplet in patients with melanoma and CNS metastases. The trial enrolled patients to 2 cohorts: those with BRAF V600–mutated disease and those with BRAF V600 wild-type disease.

However, enrollment to the BRAF V600 wild-type cohort was closed following the primary analysis of the phase 3 IMspire170 trial (NCT03273153), in which cobimetinib plus atezolizumab was not found to improve PFS compared with pembrolizumab (Keytruda) alone in patients with BRAF V600 wild-type, advanced melanoma.4

To enroll to TRICOTEL, patients were required to be at least 18 years of age and have previously untreated and histologically confirmed metastatic melanoma, and CNS metastases of at least 5 mm in at least 1 dimension. They also needed to have an ECOG performance status of 0 to 2, a life expectancy of more than 3 months, and acceptable hematological and end-organ function.

Key exclusion criteria included having received an increased corticosteroid dose in the 7 days prior to the start of study treatment; a current dexamethasone or equivalent dose of more than 8 mg per day; prior treatment with BRAF or MEK inhibitors; prior immunotherapy, except in the adjuvant setting if completed at least 90 days prior to the start of study treatment; prior whole-brain radiotherapy; and significant or uncontrolled comorbidities.

Patients enrolled to the BRAF V600 mutation–positive cohort received 840 mg of intravenous (IV) atezolizumab on days 1 and 15 of every 28-day cycle, plus 60 mg of oral cobimetinib once daily on days 1 to 21 of each cycle, and 720 mg of oral vemurafenib twice daily. Notably, atezolizumab was withheld in cycle 1 for this cohort. Of the 65 patients enrolled, 60 received treatment with all 3 agents, and 5 patients were administered only vemurafenib and cobimetinib.

“Results suggest that initial treatment with vemurafenib plus cobimetinib can reduce corticosteroid use, thereby enabling these patients to benefit from the subsequent addition of atezolizumab,” study authors noted.

In the BRAF V600 wild-type cohort, patients were given 840 mg of IV atezolizumab on days 1 and 15 of every 28-day cycle plus 60 mg of oral cobimetinib once daily on days 1 through 21 of each cycle. Treatment in both cohorts continued until disease progression, intolerable toxicity, death, withdrawn consent, or pregnancy.

The primary end point of the trial was intracranial ORR. Key secondary end points included investigator-assessed intracranial ORR; extracranial ORR and overall ORR; intracranial, extracranial, and overall disease control rate (DCR); intracranial, extracranial, and overall DOR; intracranial, extracranial, and overall PFS; overall survival (OS); safety; and quality of life.

In the BRAF V600–mutated cohort, the median age was 55 years (range, 45-65), and most patients were male (63%), White (94%), had an ECOG performance status of 0 (74%), between 1 and 3 target intracranial lesions (86%), BRAF V600E–mutated disease (83%), and extracranial lesions (80%). Rates of patients receiving antiepileptic drugs, corticosteroids, or both were 15%, 17%, and 37%, respectively.

In the BRAF V600 wild-type cohort, the median age was 63 years (range, 51-72). Most patients were female (60%), White (73%), had an ECOG performance status of 0 (67%), had between 1 and 3 target intracranial lesions (73%), and had extracranial lesions (93%). The rates of patients receiving antiepileptic drugs, corticosteroids, or both were 13%, 13%, and 47%, respectively.

Additional data showed that in the BRAF V600–mutated cohort with extracranial lesions, the investigator-assessed ORR was 58% (95% CI, 46%-71%), the DCR rate at 16 weeks was 52% (95% CI, 40%-65%), and the median DOR was 11.9 months (95% CI, 7.9-18.1). The overall ORR, 16-week DCR, and median DOR per investigator assessment were 54% (95% CI, 41%-66%), 52% (95% CI, 40%-65%), and 7.4 months (95% CI, 5.5-9.9%), respectively.

Moreover, in this cohort, the median investigator-assessed intracranial PFS and extracranial PFS was 5.8 months (95% CI, 5.4-7.4) and 9.4 months (95% CI, 6.9-13.7), respectively. The overall PFS was 5.5 months (95% CI, 5.1-7.6).

At a median follow-up of 10.0 months (range, 5.7-16.8) for patients who were receiving corticosteroids, symptomatic, or both at baseline (n = 24), the intracranial ORR was 46% (95% CI, 26%-67%) by IRC and 58% (95% CI, 37%-78%) by investigator assessment. The median intracranial DOR by IRC and investigator assessment was 9.9 months (95% CI, 4.8-12.7) and 10.2 months (95% CI, 5.6–not estimable), respectively. The median PFS per IRC and investigator assessment was 5.4 months (95% CI, 3.7-9.2) and 7.2 months (95% CI, 3.8-12.0), respectively.

At a median follow-up of 9.7 months (IQR, 6.9-14.7) for patients who had asymptomatic CNS metastases (n = 41), the intracranial ORRs per IRC and investigator assessment were 39% (95% CI, 24%-56%) and 46% (95% CI, 31%-63%), respectively. The median intracranial DOR was 7.4 months (95% CI, 3.9-11.0) and 5.7 months (95% CI, 5.5-7.6) by IRC and investigator assessment, respectively. The median PFS per IRC and investigator assessment was 5.1 months (95% CI, 3.7-7.4) and 5.5 months (95% CI, 5.4-7.4), respectively.

The triplet resulted in a median OS of 13.7 months (95% CI, 9.7-19.8) in all treated patients in the BRAFV600–mutated cohort.

Regarding safety, all 60 patients who received atezolizumab with vemurafenib and cobimetinib experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade, and 68% had at least 1 TEAE that was grade 3 or higher. The most common grade 3 or higher TEAEs were increased lipase (25%) and increased blood creatine phosphokinase (17%). Grade 3 or higher AEs of special interest included pancreatitis (28%), hepatitis (20%), creatine phosphokinase elevation (17%), and rash (15%).

One treatment-related death was reported when a patient experienced limbic encephalitis, which was related to atezolizumab. Treatment-related AEs (TRAEs) led to discontinuation of any study treatment in 27% of patients, and 2 patients discontinued atezolizumab due to infusion-related reactions. Additionally, 87% of patients needed dose modification or interruption of any study treatment due to AEs.

In the BRAF V600 wild-type cohort, grade 3 or higher TRAEs occurred in 8 of 15 patients, and the most common were anemia (13%) and dermatitis acneiform (13%). No treatment-related deaths were reported, and TRAEs led to discontinuation of any treatment in 5 patients. Twelve patients underwent dose modification or interruption due to AEs.

Study authors noted that the lack of a control group of patients with BRAF V600–mutated melanoma receiving vemurafenib plus cobimetinib made the full benefit of the addition of atezolizumab unclear. Further randomized, controlled trials are needed to fully explore the benefit of the triplet for patients with advanced melanoma and CNS metastases.

“Durable clinical benefit seen in patients with symptomatic CNS metastases suggests that the triplet combination is beneficial for this patient population with high unmet need,” the study authors concluded. “Further follow-up is needed to assess the effect of atezolizumab plus vemurafenib plus cobimetinib on OS.”

References

1. Dummer R, Queirolo P, Guijarro AMA, et al. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. Published online August 5, 2022. doi:10.1016/S1470-2045(22)00452-1
2. Garant A, Guilbault C, Ekmekjian T, et al. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review. Crit Rev Oncol Hematol. 2017;120:86-92. doi:10.1016/j.critrevonc.2017.10.009
3. Ascierto PA, Robert C, Lewis KD, et al. Time to central nervous system (CNS) metastases (mets) with atezolizumab (A) or placebo (P) combined with cobimetinib (C) + vemurafenib (V) in the phase III IMspire150 study. J Clin Oncol. 2020;38(suppl 15):10023. doi:10.1200/JCO.2020.38.15_suppl.10023
4. Gogas H, Dréno B, Larkin J, et al. Cobimetinib plus atezolizumab in BRAF V600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021;32(3):384-394. doi:10.1016/j.annonc.2020.12.004