Addition of Atezolizumab to Vemurafenib/Cobimetinib May Improve Survival in BRAF V600E-Mutated ATC

The combination use of a BRAF/MEK inhibitor plus checkpoint inhibitor immunotherapy did not meet median overall survival at 2 years, hinting at the combinations’ improved efficacy in patients with BRAF V600E-mutated anaplastic thyroid cancer.

The combination use of the BRAF inhibitor vemurafenib (Zelboraf), the MEK inhibitor cobimetinib (Cotellic), and the anti-PD-L1 checkpoint inhibitor atezolizumab (Tecentriq), or VCA, may improve survival in patients with BRAF V600E-mutated anaplastic thyroid cancer (ATC), according to data from cohort 1 of a trial (NCT03181100) presented at the 91st Annual Meeting of the American Thyroid Association.1

Maria E. Cabanillas, MD, FACE, oncologic endocrinologist, Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, presented on the data at the meeting, held October 19-23.

In cohort 1 of the trial (evaluable patients, n = 17), the overall response rate (ORR) was 72%, including 3 complete responses. “These responses were so deep and so good that we were able to remove the tumor in 8 of our patients, 6 of which are still alive,” Cabanillas said, adding that the PD-L1 score was incomplete at the moment, but 1 patient that progressed on therapy had a PD-L1 score of 0. Eight patients died at the time of data cut-off, which was September 29, 2022.

Median overall survival (OS) was not reached. The 24-month OS rate was 67% (95% CI, 40%-83%).

Investigators also conducted a post hoc analysis that compared OS in this trial to the OS from the trial2 that led to the approval of dabrafenib (Tafinlar) plus trametinib (Mekinist), or DT, which is currently FDA approved to treat this population. The 2-year OS rate was higher with VCA compared with DT (67% vs 32%, respectively).

Serious adverse events with VCA included colitis (n = 2), colonic perforation (n = 1, grade 5), optic neuritis (n = 1), rhabdomyolysis (n = 1), pancreatitis (n = 2), hepatitis (n = 3), Myasthenia Gravis (n = 1), and low EF (n = 2).

“The addition of checkpoint inhibitor immunotherapy to a BRAF/MEK inhibitor may improve survival in BRAF V600E-mutated anaplastic thyroid cancer given that the median overall survival has not been met at 2 years,” Cabanillas said. “There's a significant number of patients though that were able to undergo resection of their primary tumor due to the favorable response to treatment, and this could have contributed to the improvement in survival.”

In the trial, the investigators aimed to improve OS by combining a BRAF/MEK inhibitor plus an anti-PD-L1 immunotherapy for BRAF-mutated ATC.

“The overall survival of patients who have a BRAF mutation and are treated with BRAF-directed therapy…is much better than the patients who are not treated with BRAF therapy. There are other targetable genetic aberrations, but BRAF comprises the largest group,” Cabanillas explained. “However, there is another common target, which is PD-L1, and this is druggable with immunotherapy, so combination targeted therapy plus immunotherapies is an attractive strategy in anaplastic thyroid cancer.”

In cohort 1 of the prospective, single institution, non-randomized trial, patients received 960 mg vemurafenib twice daily plus 60 mg cobimetinib daily for a 28 day run-in, followed by the addition of 840 mg atezolizumab intravenously every 2 weeks, at which time the dose of vemurafenib was decreased to 720 mg twice daily. Of note, 2 patients who were unable to swallow the oral medications used alternative drug administration. “We allowed patients to do this so that we could include more patients in the study,” Cabanillas added.

In addition, patients could undergo surgery and radiation while on the trial.

Patients were eligible for the trial if they had unresectable locoregional or metastatic disease and adequate organ function. Patients were ineligible if they had active, known, or suspected autoimmune disease except those on hormonal replacement or vitiligo; prior treatment with an anti-PD-1 or anti-PD-L1 therapeutic antibody or pathway-targeting agents; and use of corticosteroids 10 days prior to the initiation of atezolizumab, except patients who were taking steroids for physiological replacement.

OS served as the primary end point, but these data were not presented at the meeting. Secondary end points included ORR and OS.

Of the 18 patients included, median age was 65 years (range, 44-83), and the majority were male (56%), had an ECOG status of 0 (56%), had stage IVC disease (78%), and had metastatic disease at study entry (83%).

Overall, all patients had a BRAF mutation, 61% had TP53, 56% had TERT, 28% had PIK3CA, 11% had CDKN2A, and 6% had NF2, ATM, AKT1, BRCA2, and MTOR each.

In cohort 1, median follow-up was 36.5 months (range, 2.66-61.11).

“Neoadjuvant BRAF inhibitor plus immunotherapy is being explored in a clinical trial based on the favorable results of this study,” Cabanillas concluded.

Reference:
1. Cabanillas M, Busaidy N, Zafereo M, et al. BRAF/MEK Inhibitor Plus Immunotherapy for BRAF V600E-Mutated Anaplastic Thyroid Carcinoma. Thyroid. 2022;32(1): A-136-A-174. doi:10.1089/thy.2022.29140.lb.abstracts.
2. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Onc. 2022:33(4);406-415. doi:10.1016/j.annonc.2021.12.014.