Most patients with anaplastic thyroid cancer present with locally invasive or distant metastatic disease, making potentially curative resection impossible. Chemoradiation and especially targeted therapies can slow the cancer’s progression, but responses are often cut short as the disease mutates and develops resistance; most patients die within 1 year. In hopes of prolonging responses and extending survival for patients with anaplastic thyroid cancer, a new clinical trial is adding immunotherapy to targeted therapy and cytotoxic chemotherapy regimens.
Historically, recruiting patients with anaplastic thyroid cancer for clinical trials has been difficult, in part because such patients tend to have poor performance status or comorbidities that exclude them from trials. “Most patients with anaplastic thyroid cancer aren’t eligible for clinical trials,” said Maria Cabanillas, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center.
Dr. Cabanillas and her colleagues designed a clinical trial that includes patients who have challenges associated with advanced anaplastic thyroid cancer. “We want to be able to treat the kind of patient that’s really out there,” she said. “We want the results to be applicable across the anaplastic thyroid cancer patient population.”
The clinical trial (No. 2016-0916) combines the immunotherapy drug atezolizumab with cytotoxic chemotherapy or one of three targeted therapy regimens for patients with unresectable or metastatic anaplastic thyroid cancer. The addition of immunotherapy, the researchers believe, will overcome some of the limitations of these treatments given alone.
Limitations of existing treatment
Patients with unresectable anaplastic thyroid cancer typically receive radiation with radiosensitizing chemotherapy. Chemoradiation can slow tumor growth, but radiation is not always a safe option and fails to address the metastatic disease present in 50% of patients at diagnosis.
The most common driver mutations for anaplastic thyroid cancer occur in the BRAF or RAS genes, and drugs that target the BRAF kinase have had higher response rates than cytotoxic chemotherapy. Drugs that target MEK (which shares a signaling pathway with BRAF and RAS) or VEGF (vascular endothelial growth factor) also have shown promise against the disease. However, as with cytotoxic chemotherapy, the responses to such targeted drugs are limited by the emergence of resistance mutations, which lead to disease progression.
Immunotherapy could potentially be used against anaplastic thyroid cancer, as preclinical studies have shown that anaplastic thyroid tumors express high levels of the immune checkpoint protein PD-1 (programmed cell death protein 1) and its ligand, PD-L1. However, it takes time for the immune system to respond to drugs that inhibit PD1 and PD-L1, and time is a luxury that anaplastic thyroid cancer patients do not have.
“In patients with other types of cancer, immunotherapy usually takes two or three cycles before we see a response,” Dr. Cabanillas said. “But patients with anaplastic thyroid cancer can’t wait that long because their disease is just so aggressive. Their condition would deteriorate, and they might die before we could get a response.” Immunotherapy, therefore, may be most effective given alongside drugs that are known to slow tumor growth.
The clinical trial of the PD-L1 inhibitor atezolizumab plus targeted therapy or cytotoxic chemotherapy (No. 2016-0916) began enrolling patients with unresectable or metastatic anaplastic thyroid cancer in July 2017. The trial is also enrolling a small number of patients with unresectable or metastatic poorly differentiated thyroid cancer, which, like the anaplastic variant, is uncommon and aggressive.
Patients in the trial undergo molecular testing for BRAF and RAS mutations and immediately begin treatment with nanoparticle albumin–bound paclitaxel or standard paclitaxel to impede disease progression while they wait for the test results, which can take up to 3 weeks.
Once the molecular test results arrive, patients are assigned to treatment cohorts on the basis of their genetic mutations (see schema, above). Patients with BRAF mutations are assigned to cohort 1 and receive the BRAF inhibitor vemurafenib, the MEK inhibitor cobimetinib, and the immunotherapy drug atezolizumab. Patients with RAS mutations are assigned to cohort 2 and receive cobimetinib and atezolizumab. Patients with neither mutation are assigned to cohort 3 and receive the VEGF inhibitor bevacizumab and atezolizumab. Patients who are ineligible for any of these 3 cohorts are assigned to cohort 4 and treated with standard or nanoparticle albumin–bound paclitaxel and atezolizumab. Patients may receive radiation therapy if needed; this is decided on a case-by-case basis.
Patients with risk factors or comorbidities that preclude treatment with a drug used in one cohort are assigned to another cohort. “We want to match both the tumor and the appropriate medical condition,” Dr. Cabanillas said. “We don’t want to treat a patient with a drug that might worsen a medical problem.”
Despite the rarity of both anaplastic and poorly differentiated thyroid cancers, Dr. Cabanillas believes that the trial will be able to complete its planned enrollment of 50 patients, at least 36 of whom must have anaplastic thyroid cancer. “We designed the atezolizumab trial to be available to about 90% of the new anaplastic thyroid cancer patients we see,” she said. She added that MD Anderson’s Anaplastic Thyroid Cancer Clinic has a multidisciplinary program—Facilitating Anaplastic Thyroid Cancer Specialized Treatment, or FAST—that expedites the evaluation of patients with the disease and helps enroll them in clinical trials if appropriate (see Anaplastic Thyroid Cancer, OncoLog, April 2016).
Dr. Cabanillas emphasized the need for immediate referral of patents with suspected anaplastic thyroid cancer to a large cancer center. “If patients are referred early, we can probably get them into a clinical trial of a targeted agent plus immunotherapy,” she said. “We feel like that is the best treatment strategy for anaplastic thyroid cancer.”
For more information, contact Dr. Maria Cabanillas at 713-792-2841 or firstname.lastname@example.org. For more information about the clinical trial of immunotherapy plus targeted or cytotoxic therapy for patients with anaplastic or poorly differentiated thyroid cancer, visit www.clinicaltrials.org and search for study No. 2016-0916. For more information about MD Anderson’s Anaplastic Thyroid Cancer Clinic, visit http://bit.ly/1RO2jxL.
OncoLog, September 2017, Volume 62, Issue 9