Researchers have demonstrated that anti–PD-L1 immunotherapy combined with mutation-directed targeted therapy may improve overall survival in patients with anaplastic thyroid carcinoma, according to a recent study published by Cabanillas et al in JAMA Oncology.
Background
Anaplastic thyroid carcinoma—a rare and aggressive malignant tumor with a poor prognosis—often develops from differentiated thyroid cancer subtypes such as papillary and follicular thyroid carcinomas, each of which has distinct driver mutations that can influence tumor behavior and progression. BRAF mutations have therapeutic and prognostic implications and are seen in 40% of thyroid cancer cases.
Study Methods and Results
In the single-center phase II trial, the researchers assigned 18 patients with BRAF-mutated anaplastic thyroid carcinoma to receive the immune checkpoint inhibitor atezolizumab plus the mutation-matched targeted therapy combination of vemurafenib and cobimetinib (cohort 1), 21 patients with RAS-mutated (NRAS, KRAS, or HRAS) or NF1/2-mutated anaplastic thyroid carcinoma to receive atezolizumab plus cobimetinib (cohort 2), and 3 patients with anaplastic thyroid carcinoma with no mutations to receive atezolizumab plus bevacizumab (cohort 3).
The researchers found that the median overall survival across all three cohorts was 19 months, which compared favorably with the historical overall survival of 5 months in this patient population. The longest overall survival among the cohorts was 43.2 months in patients with BRAF V600E mutations—the longest overall survival to date for systematic therapy in anaplastic thyroid carcinoma. The median overall survival was 43.2, 8.7, and 6.2 months, and the objective response rates were 50%, 14%, and 33% in cohorts 1, 2, and 3, respectively.
The researchers noted that although it has historically been challenging to enroll patients with anaplastic thyroid carcinoma in clinical trials, the recent study had more permissive entry criteria that contributed to successful enrollment. For instance, the trial allowed patients to continue receiving chemotherapy during screening, given the potential for rapid disease progression. Additionally, the researchers allowed patients to administer the oral drugs through a feeding tube using alternative formulations.
The researchers reported that the observed side effects were expected based on previous trials with these drugs. The most common adverse events among all three cohorts were fatigue, lymphopenia, diarrhea, and anemia. There were notable serious side effects in a few patients, including colonic and esophageal perforations.
Conclusions
“Patients with anaplastic thyroid carcinoma need treatments that work fast, and we saw promising results with this combination treatment approach. The takeaway from this study is that immunotherapy really does add benefit for patients,” highlighted lead study author Maria Cabanillas, MD, Professor of Endocrine Neoplasia & Hormonal Disorders at The University of Texas MD Anderson Cancer Center. “Based on these findings, we currently use this combination as our standard of care at MD Anderson for patients with [anaplastic thyroid carcinoma] and BRAF mutations,” she underscored.
Limitations of the study included the absence of a control arm, a difficulty often faced in rare tumor trials, as well as the acceptance of radiation therapy and surgery to remove the primary tumor—which may have contributed to the improvement in survival. However, the researchers argued that future anaplastic thyroid carcinoma clinical trials should be designed to allow for surgery, as it may have contributed to the improved survival outcomes in this study.
“There are no approved and effective therapies for [anaplastic thyroid carcinoma] with non-BRAF mutations, and we continue to focus our research in that area. We are working to optimize outcomes for our patients. We want them to live longer and better lives, and this study offers hope for patients with [anaplastic thyroid carcinoma],” Dr. Cabanillas concluded.
Disclosure: The research in this study was supported by Genentech, The University of Texas MD Anderson Cancer Center’s Rare Tumor Initiative as part of the institution’s Strategic Research Initiative Development (STRIDE) program, and the National Institutes of Health. For full disclosures of the study authors, visit jamanetwork.com.
