Nivolumab As Salvage Therapy Signals Response in Patients With Heavily Pretreated Gynecologic Cancers

Heather Williams, MD

Heather Williams, MD

A retrospective study conducted at the Georgia Cancer Center in Augusta examined overall response and progression-free survival (PFS) in heavily pretreated patients with gynecologic malignancies who had received checkpoint inhibition therapy with nivolumab (Opdivo) in the salvage setting.

Twenty-eight patients with different gynecologic malignancies, including cervical cancer, uterine cancer, and ovarian cancer, were identified for this study. All patients had received at least 4 prior lines of chemotherapy and were fit for further therapy.

The median PFS for all patients was 2.6 months. However, 25% of patients received 4 or more cycles and had a significantly different PFS than those who discontinued therapy after 2 to 3 cycles (2.6 vs 6.4 months;P= .0005).

Depending on the type of malignancy, physicians saw some variances in patient response. Specifically, patients with uterine cancer (n = 9) had the lowest response rate with only one patient showing a response to the therapy. For ovarian cancer (n = 5), on the other hand, all but one patient responded to the treatment. Differences were also noted according to patients’ microsatellite instability (MSI) and PD-1/PD-L1 status.

Sixty-eight percent of patients experienced adverse events, including; fatigue (46.4%), arthralgia (25%), and anemia (21.4%). Most adverse events were manageable with one exception, a grade 3-4 case of diffuse maculopapular rash. All patients, excluding one who experienced diffuse maculopapular rash, were able to continue treatment.

These data signal that the checkpoint inhibitor nivolumab may provide meaningful palliation in patients with heavily pretreated gynecologic cancers.

Heather Williams, MD, a gynecologic oncology fellow, Augusta University Medical College of Georgia, provided background on the study of nivolumab as salvage therapy in heavily pretreated patients with gynecologic malignancies in an interview withTargeted Oncology.

TARGETED ONCOLOGY: Can you explain the rationale behind this retrospective study?

Williams: We had been giving this as a palliative option to some of our patients in the clinic who were heavily pretreated and didn't have any other options. We noticed that some patients had a response, so we decided [to review the patients that had received the treatment] between 2015 and 2018 to see what their overall response was and see if there was an impact on their PFS.

TARGETED ONCOLOGY: What are outcomes typically like for women with heavily pretreated gynecologic cancers?

Williams: At that point, a lot of these patients were platinum resistant. [This was also a mix of cancers, including uterine, cervical, and ovarian]. A lot of older chemotherapy drugs are usually given to these patients and they have a historical response rate of around 10% to 20% pending the cancer subtype.

TARGETED ONCOLOGY: What were the findings of this study?

Williams: We found that 7 out of 28 patients had a partial response or stable disease after 3 cycles, that's about 25%. The median PFS for those 7 patients that were responders was 6.6 months in comparison to the other patients who showed a PFS of 2.5 months.

Additionally, we saw a response in 4 patients who had low-grade serous ovarian cancer. Their median PFS was 6.1 months with a range of 3.8 to 25 months, which we thought was pretty interesting. Low-grade serous carcinoma is typically a slow-growing cancer that is difficult to treat, even in the frontline setting. It was promising to see a response to an immune checkpoint inhibitor [in these patients], especially when they had received several prior lines of therapy. [As far as] the low-grade serous patients, none of them were PD-L1— or PD-1–positive or MSI high. 

We also had one patient with MSI-high uterine cancer who had a response and a patient with MSI-high cervical cancer who had a response.

It's also important to note that in this group of [patients] who were heavily pretreated, they tolerated this treatment well. Most commonly, they reported fatigue at a rate of about 46%. Then, arthralgia or joint pain at a rate of about 25% and anemia was noted about 21% of the time. Only one patient stopped treatment as a result of a grade 3 to 4 event of diffuse maculopapular rash.

[We concluded from this study] that for patients with heavily treated gynecologic malignancies who may not always have the best performance status, but are willing and able to get treatment, we believe that immune checkpoint inhibitor therapy did provide meaningful palliation of their disease in this subset of patients.

TARGETED ONCOLOGY: Were there any malignancies in this study that responded to nivolumab savage therapy better than others?

Williams: We cannot make that conclusion with this retrospective study. [However], the 2 patients that were MSI high, [one with uterine and the other with cervical cancer had significant responses]. With uterine, the patient received treatment for 8 months and the patient with cervical cancer stayed on this drug for 28 months. Additionally, there was 5 low-grade serous patients in the study and 4 had either stable disease or a partial response ranging from 3.8 to 25 months.

TARGETED ONCOLOGY: What combination therapies including nivolumab do you think could benefit this patient population in a different study?

Williams: [Researchers] are looking at combinations with nivolumab and PARP inhibitors, other immune checkpoint inhibitors, such as the CTLA-4 inhibitors, anti-angiogenic agents, and other molecular targeted therapies. There are a couple of phase II studies that have been reported that showed promising results with a higher response rates with combination therapy. I definitely think these [combinations] hold promise and will hopefully demonstrate meaningful response rates and progression-free survival.

TARGETED ONCOLOGY: How do you see checkpoint inhibition changing the treatment of gynecologic malignancies in the next few years?

Williams: I think it will become an option; however, I don't believe that single-agent use will be as beneficial as a combination therapy in patients whose PD-L1 and MSI status are unknown or in patients who are PD-L1—negative or MSI-stable. [However, I do think that there is promise with single agents for patients with PD-L1–positivity or MSI-high.

Reference:

Williams H, Wang J, Tran L, et al. Use of nivolumab as salvage therapy in heavily pretreated patients with gynecologic malignancies.J Clin Oncol. 2019;37(suppl 15; abstr 5593). doi: 10.1200/JCO.2019.37.15_suppl.5593.