New treatments lacking in adrenocortical cancer

Novel therapy development in adrenocortical cancer (ACC) has been marked by one setback after another, Tito A. Fojo, MD, PhD, explained during a discussion at the 38th Annual CFS meeting.¹

Surgery remains the only curative modality for this rare disease; however, 60% to 70% of patients eventually relapse after undergoing surgery, making novel therapeutics an area of high unmet medical need.

Tito A. Fojo, MD, PhD

Several targeted therapies for ACC have been explored in clinical trials, but thus far, targeted agents as a whole have been a “major disappointment in ACC,” said Fojo, co-director, Adrenal Center, NewYork-Presbyterian/Columbia University Irving Medical Center.

Sequencing data from genomic characterization of ACC has also failed to yield new outlets for treatment advances. “No clear (frequent) genomic drivers have been identified,” said Fojo, “The likelihood of significant therapeutic advances emerging from the sequencing studies is very low—we must look elsewhere for therapeutic ideas.”

Limited immunotherapy activity

Analyses have shown a high incidence of mutations in ACC, indicating the potential for a high tumor mutational burden (TMB). High TMB can correlate with strong immunotherapy activity; however, Fojo said immune checkpoint inhibitors have shown little to no activity in ACC.

In a phase 1b expansion cohort from the JAVELIN solid tumor trial, 50 patients with metastatic ACC and prior platinum-based therapy received monotherapy with the PD-L1 inhibitor avelumab (Bavencio).² The objective response rate (ORR) was 6%, comprising all partial responses. Although the study investigators found their results to show a positive signal, Fojo said, “I, quite frankly, would beg to differ. I don’t consider a 6% response rate as very meaningful.”

The PD-1 inhibitor nivolumab (Opdivo) also fell short in ACC. A single-arm, multicenter phase 2 trial examined the immune checkpoint inhibitor in 10 patients with metastatic ACC who had either prior platinum-based chemotherapy and/or mitotane, or had declined frontline chemotherapy.³ Nivolumab induced a response in only 1 patient. It was an unconfirmed partial response and the patient eventually discontinued the study due to an adverse event. “Again, here, although the authors considered that there was ‘modest antitumor activity,’ I would say that 1 out of 10 responses is not something that I would consider to be meaningful,” said Fojo.

The response rate was somewhat improved with the PD-1 inhibitor pembrolizumab (Keytruda). In a phase 2 study, patients at Memorial Sloan Kettering Cancer Centerwith advanced ACC received single-agent pembrolizumab.⁴ There was no restriction on prior therapy. Overall, 9 (23%) of 39 patients had an objective response. Despite the increased ORR compared with other immune checkpoint agents, Fojo said, “This is not something that is likely to be reproduced and, keep in mind, this was a single-institution trial.”

Given the disappointing data from these trials, Fojo said that, clinically, he only tries immunotherapy in patients who have “failed all of our standard approaches,” and that, unfortunately, “All too often, immunotherapy is being used before chemotherapy and I would not do that.”

Chemotherapy and surgery

Given the lack of progress with novel therapies, Fojo said, “At the end of the day, we are still relying on conventional chemotherapy. It is active in about 20% to 30% of patients, who will have meaningful responses and usually will then have an overall survival that is somewhat better.”

Fojo added that surgery remains paramount in the ACC armamentarium. “Of all the things that we do—chemotherapy, immunotherapy, targeted therapy, sequence-directed therapy—surgery is still the most important thing. And you must try, whenever possible, to get your patients to surgery.”

Fojo concluded with 2 additional pieces of clinical advice for physicians to bring back to their practice. The first was to not perform laparoscopic resection in patients with ACC. “These [procedures] often lead to a high incidence of disseminated peritoneal carcinomatosis.” He cited a retrospective analysis that found that 25 (55.6%) of 34 patients with ACC who received laparoscopic resection had peritoneal dissemination compared with only 7 (3%) of 222 patients who underwent open resection.⁵

And Fojo’s final advice was to always make sure to manage hormones in patients with ACC. “Many of the patients have excess hormones being produced by their tumor. Please don’t forget to manage that, and manage it aggressively, because Cushing's disease from a tumor that’s produced a large number of hormones is a very difficult thing to endure. [Manage hormones] yourself and in combination with an endocrinologist.”

References

1. Fojo TA. Adrenal Cancers: What Is New? Presented at: 38th Annual CFS. November 4-6, 2020.

2. Le Tourneau C, Hoimes C, Zarwan C et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer. 2018;6(1):111. doi: 10.1186/s40425-018-0424-9

3. Carneiro BA, Konda B, Costa RB, et al. Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. Clinical Trial J Clin Endocrinol Metab. 2019;104(12):6193-6200. doi: 10.1210/jc.2019-00600

4. Raj N, Zheng Y, Kelly V, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol. 2020;38(1):71-80. doi: 10.1200/JCO.19.01586

5. Payabyab EC, Balasubramaniam S, Edgerly M, et al. Adrenocortical cancer: a molecularly complex disease where surgery matters. Clin Cancer Res. 2016;22(20):4989-5000. doi: 10.1158/1078-0432.CCR-16-1570