Pembrolizumab Continues to Show Modest Clinical Activity in Advanced Ovarian Cancer

Ursula A. Matulonis, MD

Pembrolizumab (Keytruda) demonstrated modest clinical activity in patients with advanced recurrent ovarian cancer, according to final results of the phase 2 KEYNOTE-100 trial that were presented during the 2020 ASCO Virtual Scientific Program.

In the study, 376 patients with advanced recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were enrolled onto 2 cohorts: patients who received 2 or fewer prior lines of chemotherapy and had a platinum-free or treatment-free interval (PFI/TFI) of 3 to 12 months (cohort A) or those who received 3 to 5 prior lines of chemotherapy and had a PFI/TFI of 3 months or longer (cohort B). All patients received 200 mg of pembrolizumab for 2 years, or until disease progression, death, or unacceptable toxicity.

After a median follow-up of 37.8 months, results showed that the objective response rate (ORR) was 8.5% in all-comers, which comprised of 7 complete responses and 25 partial responses. The responses were not found to differ when stratified by lines of chemotherapy or PFI/TFI. However, there did appear to be a trend toward increased ORRs in patients with high PD-L1 expression (combined positive score [CPS] 10 or higher) across both cohorts, at 11.6% in cohort 1 and 18.2% in cohort B. Overall, the median duration of response was 10.2 months (range, 3.3+ to 35.4+).

The median progression-free survival (PFS) was 2.1 months in both cohorts. In cohorts A and B, the median overall survival (OS) was 18.7 months and 17.6 months, respectively.

“We found that, regardless of the degree of platinum sensitivity, there were no differences in the responses,” said lead study author Ursula A. Matulonis, MD. “This was very important. Most of our patients had high-grade serous cancer, however, there were also patients with clear cell cancer. The patients with clear cell cancer demonstrated a trend towards a higher response rate.”

In an interview with OncLive, Matulonis, professor of medicine at Harvard Medical School, medical oncologist and chief of the Division of Gynecologic Oncology at the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discussed the final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer.

OncLive: Could you discuss recent therapeutic advances in ovarian cancer?

Matulonis: There is a lot going on for patients with ovarian cancer and treatment paradigms are frequently changing, especially for women who are newly diagnosed. Just a few weeks ago, there were 2 FDA approvals. PARP inhibitors were approved for use, after the completion of chemotherapy, in patients with newly diagnosed advanced ovarian cancer. In addition to this, the PAOLA-1 trial added olaparib (Lynparza) to bevacizumab (Avastin) in the newly diagnosed setting.

In terms of patients with recurrent disease, many different avenues and treatments are currently being tested. Some of these data was presented at the 2020 ASCO Virtual Scientific Program. The treatment landscape for ovarian cancer is truly booming with activity right now. Investigators are now wondering: how robust are these results? How do they affect PFS and OS? What toxicities are the patients experiencing?

Could you elaborate on the historical challenges of immunotherapy in ovarian cancer?

Over a decade ago, multiple trials showed that newly diagnosed patients that exhibited T-cell infiltration did better than those who did not; they had an improved OS. Investigators now understand that the immune system plays a role in how cancer behaves. In addition to this, early results of ipilimumab (Yervoy) showed that a few patients had prolonged responses to the single agent.

When analyzing different checkpoint inhibitors in patients with recurrent ovarian cancer, the results are not overwhelming. They only seem to show moderate activity. Back in 2015, we started with a very small trial of nivolumab (Opdivo), and this showed about a 15% response rate. In 2019, data from single-agent avelumab (Bavencio) showed a response rate of 10%.

Additionally, updated data from the KEYNOTE-100 trial, which had a follow-up of over 30 months, studied single-agent pembrolizumab in 376 patients with advanced/recurrent ovarian cancer. The overall response rate was 8%. For patients with predominately platinum-resistant ovarian cancer, response rates with chemotherapy were quite low as well. In some instances, response rates with chemotherapy in the platinum-resistant setting is 0%. For example, in the AURELIA trial, topotecan had a response rate of 0% when used alone. Although, with the addition of bevacizumab, the response rate increased.

The use of liposomal doxorubicin demonstrated similar results, with response rates between 5% and 10%. Ultimately, this is a challenging patient population to treat.

In the KEYNOTE-100 trial, patients were broken up into 2 groups. Patients in group A were less heavily pretreated and received at least 1 to 3 prior lines of treatment; they had to have a PFI of at least 3 to 12 months. Conversely, patients in group B were more heavily pretreated. This group of patients could receive up to 6 lines of prior treatment and had to have a PFI of 3 months or greater.

Another factor was the level of PD-L1 expression. This is defined by a CPS, which looks at the PD-L1 expression in all types of cells. For CPS scores of 10 or higher, response rates were just below 20%.

In this study, the responses were similar, regardless of the number of prior lines of therapy. The level of platinum sensitivity also did not predict the responsiveness.

What does this mean for any potential role for pembrolizumab in clinical practice?

[In ovarian cancer], pembrolizumab does not yet have FDA approval. Its current approval is based on its FDA approval of microsatellite instability–high (MSI-H) tumors. The issue is, most of our patients have high-grade serous cancer, they do not have MSI-H tumors. In fact, only 8% of all ovarian cancers will have a MSI-H tumor. For high-grade serous cancer, MSI-H status is in about 2% to 3% of patients. This being said, that FDA approval of pembrolizumab in MSI-H tumors does not encompass most of our patients with advanced recurrent ovarian cancer. Currently, pembrolizumab, as well as other immunotherapy agents, are being tested as combination therapies.

There is certainly a lot going on in this space. Investigators are now trying to deduce the best way to incorporate immune-oncology agents into treatment plans for patients with microsatellite stable (MSS) tumors.

Have any new safety signals emerged in the KEYNOTE-100 trial?

There were no newly discovered safety signals in this trial. A majority of toxicities were fatigue, nausea, hyperthyroidism, hypothyroidism, colitis, etc. These are toxicities that are commonly seen when using immuno-oncology agents.

What is the main takeaway from this longer follow-up?

This study showed moderate activity in patients with recurrent or platinum-resistant ovarian cancer, regardless of the level of platinum sensitivity or the number of prior lines of treatment. This is much different than chemotherapy. In chemotherapy, response rates drop significantly depending on how heavily pretreated the patients are. That’s not what we’re seeing in this trial; we’re seeing very uniform levels of responsiveness.

Reference

1. Matulonis UA, Shapira R, Santin A, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6005. doi:10.1200/JCO.2020.38.15_suppl.6005