Cracking the Immunotherapy Code Remains a Challenge in Ovarian Cancer

Martin Cannon, PhD

Despite the successes observed with the use of immunotherapy among various cancer histologies, immune checkpoint inhibitors remain broadly ineffective in the treatment of patients with ovarian cancer. Although finding an effective use for these agents in this patient population has been challenging, altering the tumor microenvironment could be the key to generating activity with immunotherapy in patients with ovarian cancer, Martin Cannon, PhD, detailed.

“There are 2 areas you have to cover. Firstly, you need to stimulate antitumor T cells. That's the basic requirement for these drugs. Moreover, you likely need to alleviate local immune suppression in the tumor microenvironment, and that is a big deal for ovarian cancer. Ideally, if you do both of those, then you might be in good shape and get a response [with immunotherapy],” Cannon said following an OncLive^® State of the Science Summit™ on gynecologic oncology.

Prior studies of immune checkpoint inhibitors for patients with platinum-resistant ovarian cancer have generated underwhelming results, according to Cannon. In a small phase 2 trial (UMIN000005714) that was believed to be the first to evaluate nivolumab (Opdivo) in this patient population, evaluable patients (n = 20) experienced an overall response rate (ORR) of 15%.¹

Moreover, the phase 2 KEYNOTE-100 study (NCT02054806) evaluated the antitumor activity and safety of pembrolizumab (Keytruda) in patients with advanced recurrent ovarian cancer.² Cohort A (n = 285) evaluated patients who received 1 to 3 prior lines of treatment with a platinum-free interval between 3 and 12 months, and cohort B (n = 91) evaluated patients who were given 4 to 6 prior lines of treatment with a platinum-free interval at least 3 months. The ORR was 7.4% for cohort A and 9.9% for cohort B.

In the interview, Cannon detailed the history of investigating immune checkpoint inhibitors in patients with ovarian cancer and expanded on the questions that need to be answered to potentially improve the activity of these agents in this patient population. Cannon is a professor of Microbiology and Immunology at the University of Arkansas for Medical Sciences (UAMS), UAMS College of Medicine, in Little Rock.

OncLive: Could you expand on the conundrum of immunotherapy in ovarian cancer?

Cannon: The first key point is that [immunotherapy] doesn't work [in patients with ovarian cancer], or at least that’s the broad perception. Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and related agents, have been a total bust when it comes to the treatment of [patients with] ovarian cancer. That's the clinical problem that acutely needs to be addressed.

What data have pointed to the lack of efficacy of immune checkpoint inhibitors in the treatment of patients with ovarian cancer?

There was an early [phase 2] trial published in the Journal of Clinical Oncology in 2015 reporting on a small clinical trial [evaluating] nivolumab in patients with platinum-resistant ovarian cancer, and [these patients experienced] a 15% overall response rate. [Of the 3 responders], 1 patient had a partial response and there were 2 complete responses.1 It wasn't a great start, and it wasn't very encouraging.

The pivotal study was the KEYNOTE-100 study, published by Ursula A. Matulonis, MD, [of Dana-Farber Cancer Institute], and colleagues, in the Annals of Oncology in 2019. They found that in patients [in cohort A who received] 1 to 3 prior lines of treatment with a platinum-free interval between 3 and 12 months, pembrolizumab [elicited] an ORR of 7.4%, which was pretty dismal. In a similar vein, in those patients [in cohort B who received] 4 to 6 prior lines of treatment, pembrolizumab [generated an ORR of 9.9%]. [Those findings essentially] shot down the prospect of using immune checkpoint inhibitors in [patients with] ovarian cancer because it looked to be futile.

Why do immunotherapy approaches remain largely ineffective for patients with ovarian cancer? What are the potential explanations for this?

It is a bit of a puzzle. As many people are aware, immune checkpoint inhibitors are broadly used for [patients with] a variety of cancers, and very often, to considerable effect, they do work. One thing to remember for immune checkpoint inhibitors: they're not targeting the cancer itself. They're targeting T-cell responses. Therefore, if a patient doesn't have that T-cell response to the tumor and it is not intrinsically present in the first place, then it is a waste of time using checkpoint inhibitors.

It could be that in ovarian cancer, there may not be significant antitumor T-cell response for these drugs to work on. That could be due to low tumor mutational burdens [and a lack of] antigens to stimulate T cells, leading to limited immunogenicity. It could be also be immune suppression in the tumor microenvironment. Those T cells [may be] there, potentially even regulatory T cells, which are profoundly immunosuppressive. It's not a helpful situation, and you have to fix that up front before you come in with pembrolizumab, nivolumab, or any other immune checkpoint inhibitors.

References

1. Hamanishi J, Mandai M, Minami M, et al. Safety and antitumor activity of anti–PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(suppl 34):4015-4022. doi:10.1200/JCO.2015.62.3397
2. Matulonis UA, Shapira-Frommer RS, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135