Given either alone or in combination with chemotherapy PFS, OS not improved, study suggests

Avelumab, an immune checkpoint inhibitor, given alone or in combination with chemotherapy, failed to improve either progression-free or overall survival (OS) compared with chemotherapy alone in women with platinum-resistant or platinum-refractory ovarian cancer, a randomized, phase III study found.

In a cohort of 566 patients, median progression-free survival (PFS) was 3.7 months (95% CI, 3.3-5.1 months) in patients randomized to avelumab plus pegylated liposomal doxorubicin (PLD) compared with 3.5 months (95% CI, 2.1-4.0 months) in the PLD alone group and 1.9 months (95% CI, 1.8-1.9 months) in the immune checkpoint inhibitor alone arm, Eric Pujade-Lauraine, MD, ARCAGY-GINECO, Paris, and colleagues reported in the Lancet Oncology.

Median OS was 15.7 months (95% CI, 12.7-18.7 months) in the combination group versus 13.7 months (95% CI, 11.8-15.5 months) in the PLD group and 11.8 months (95% CI, 8.9-14.1 months) in the avelumab group, investigators added.

“To our knowledge, this is the first phase III trial of an immune checkpoint inhibitor in patients with platinum-resistant or platinum-refractory ovarian cancer to be reported,” Pujade-Lauraine and colleagues wrote. They also noted that they did identify subpopulations in which future studies of immune checkpoint inhibitors in combination with PLD might be warranted.

The JAVELIN Ovarian 200 study was carried out at 149 hospitals and cancer treatment centers in 24 countries. Patients had epithelial ovarian, fallopian tube, or peritoneal cancer and had received a maximum of three previous lines of treatment for platinum-sensitive disease. Approximately half of the cohort had primary resistance to platinum while one-quarter had platinum-refractory cancer.

Patients were assigned to avelumab, at a dose of 10 mg/kg given intravenously every two weeks, or avelumab plus PLD at a dose of 40 mg/m2, every four weeks.

“Antihistamine and acetaminophen premedication was mandatory 30-60 minutes before avelumab infusions but was optional before PLD infusions,” the investigators wrote.

The median duration of treatment was approximately 16 weeks in the PLD arms compared with a median of only about 10 weeks for the immune checkpoint inhibitor arm.

Objective responses were confirmed in 13% (95% CI, 9-19%) in the combination group and 4% (95% CI, 2-8%) in each of the other two treatment arms.

At a median follow-up of approximately 18 months, 71% of patients in the combination arm had disease progression or died compared with 66% of patients in the PLD alone group and 82% of those in the avelumab group, as investigators observed. Over half of patients in each of the 3 treatment groups had died at study endpoint, they added.

A large majority of the cohort were evaluable for programmed cell death-ligand 1 (PD-L1) expression, some 57% of whom had PD-L1-positve tumors.

“Unstratified HRs for progression-free survival by blinded independent central review versus PLD in the PD-L1-positive subgroup were 0.65 (95% CI 0 46-0 92) for the combination and 1.45 (1.03-2.04) for avelumab,” the study authors wrote. “Unstratified HRs for overall survival versus PLD in the PD-L1-positive subgroup were 0.72 (0.49-1.05) for the combination and 0.83 (0.57-1.23) for avelumab.”

Approximately half of patients (228 of 300) had CD8-positive tumors as well.

“Unstratified HRs for progression-free survival by blinded independent central review versus PLD within the CD8-positive subgroup were 0.64 (95% CI 0.44-0.95) for the combination and 1.58 (1.09-2.29) for avelumab. Unstratified HRs for overall survival versus PLD within the CD8-positive subgroup were 0.66 (0.43-1.02) for the combination and 1.03 (0.67-1.57) for avelumab,” the study authors wrote.

The incidence of serious treatment-related adverse events was relatively low at 18% in the combination group, 11% in the PLD alone group and 7% in the immune checkpoint inhibitor arm.

“Consistent with the poor prognosis in this patient population, approximately 50% of patients in all groups died, had disease progression, or withdrew from the study within 2 months of randomization,” the investigators observed.

However, in patients with tumors that were positive for PD-L1, CD8, or both, benefit from the combination treatment did appear to be greater relative to the other two treatment arms, even though this finding should be interpreted with caution as these subgroups were underpowered for analysis, as the authors noted.

Commenting on the findings, Emma Barber, MD, and Daniela Mateo, both from Northwestern University in Chicago, cautioned that neither PFS nor OS were improved with either avelumab alone or avelumab plus PLD compared with PLD alone either in the main analysis or in the predefined PD-L1-positive or CD8-positive subsets. At the same time, they acknowledged that in patients whose tumors expressed either PD-L1 or CD8-positive cells, the HR for both endpoints were significantly in favor of the combination.

“In other tumor types, chemotherapy had been shown to induce antigen presentation, priming tumor cells to become receptive to the immune attack triggered by PD-L1 inhibitors and yielding improved clinical outcomes,” they wrote. Thus, there was a solid rational for testing immune checkpoint inhibitors with chemotherapy in ovarian cancer, as they suggested.

“Javelin-200 was a well designed and conducted trial, addressed a legitimate question and, yet, yielded solidly negative results,” the editorialists underscored.

Nevertheless, these are not the only negative findings of immunotherapy in ovarian cancer as they mirror those from the phase III IMagyn500 study where neither PFS nor OS were improved for patients with newly diagnosed ovarian cancer randomized to additional atezolizumab plus carboplatin-paclitaxel-bevacizumab compared to those treated with carboplatin-paclitaxel-bevacizumab alone, as they pointed out.

“Whether dual expression of CD8 and PD-L1 truly identifies an immune responsive subgroup of patients remains to be validated but represents a new starting point,” Barber and Matei suggested, and added, “We hope that the focus on rational combinations and the use of sophisticated real-time biomarkers will [eventually] lead to long-awaited success.”

  1. Immune checkpoint inhibitor alone or in combination with chemotherapy did not improve progression-free or overall survival in patients with platinum-resistant/refractory ovarian cancer.

  2. The benefit of combining immunotherapy plus chemotherapy appeared to be greater in patients with PD-L1, CD8-positive tumors compared with either treatment alone.

Pam Harrison, Contributing Writer, BreakingMED™

The study was funded by Pfizer and Merck KGaA, Darmstadt, Germany.

Disclosures: Pujade-Lauraine reported having received personal fees from AstraZeneca, Clovis Oncology, Incyte, Pfizer, Roche, and Tesaro and is the chair of ARCAGY-Research.

The editorialists declared no conflicts of interest.

Cat ID: 692

Topic ID: 78,692,730,692,693,192,925