Expert Says Phase III Avelumab Trial is First Step of Immunotherapy Story in Ovarian Cancer

Eric Pujade-Lauraine, MD, PhD

Eric Pujade-Lauraine, MD, PhD

Immune checkpoint inhibitor avelumab (Bavencio) as monotherapy or in combination with pegylated liposomal doxorubicin (PLD) did not lead to improved survival in the overall population of patients with platinum-resistant or -refractory epithelial ovarian cancer compared with PLD alone in the JAVELIN Ovarian 200 trial, which was presented at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, however, certain subgroups did benefit the combination.

In the multicenter, randomized phase III JAVELIN Ovarian 200 trial, 556 patients with platinum-resistant or -refractory ovarian cancer were randomized to receive either avelumab alone, avelumab in combination with PLD, or PLD alone. The primary end points were superior overall survival (OS) or progression-free survival (PFS) for either avelumab arm versus PLD. A secondary end point was objective response rate (ORR).

The ORR was 13.3% with the avelumab combination (95% CI, 8.8%-19.0%), 3.7% with the immunotherapy as a single agent (95% CI, 1.5%-7.5%), and 4.2% with PLD alone (95% CI, 1.8%-8.1%). Avelumab did not lead to any new safety signals in either arm.

The combination led to a hazard ratio (HR) of 0.78 for PFS, which missed the prespecified criteria for superiority. OS for the combination was not met (HR, 0.89; RCI 0.744-1.241; one-sideP= .2082). In the single-agent avelumab arm, the PFS end point (HR, 1.68; RCI, 1.320-2.601; one-sided Pvalue >.99) and the OS endpoint (HR, 1.14; RCI, 0.948-1.580; one-sided Pvalue = .8253) were both missed.

According to an exploratory biomarker analysis, patients who were PD-L1—positive received benefit with the addition of avelumab versus chemotherapy alone. The ORR was 18.5% in patients from the PD-L1–positive subgroup (95% CI, 11.1-27.9) while the ORR was 3.4% in those who were PD-L1–negative (95% CI, 0.4-11.9). Trends in PFS and OS favored the PD-L1–positive subgroup versus the PD-L1–negative with the combination regimen. However, further validation is needed, according to Eric Pujade-Lauraine, MD, PhD, lead investigator on the trial.

In an interview withTargeted Oncology, Pujade-Lauraine, a medical oncologist at Université Paris Descartes in France, discussed the data from the JAVELIN Ovarian 200 trial, which he presented at the 2019 SGO Annual Meeting. He highlighted the need for biomarkers in this space, as well as some data from an exploratory analysis from this trial.

TARGETED ONCOLOGY: Could you provide some background to this study?

Pujade-Lauraine:This is the first phase III trial of an immune checkpoint inhibitor in ovarian cancer. While we have a lot of data suggesting that the immune system is very important in ovarian cancer and the prognosis of ovarian cancer, there was a lot of excitement when checkpoint inhibitors came into research. However, ovarian cancer does not have the same tumor mutational burden as in lung cancer or melanoma.

The first data were disappointing and lower than we expected. There was less than 10% rate of response in the heavily pretreated patients. This trial is the first to combine a checkpoint inhibitor with a chemotherapy. It was expected that there would be synergy, allowing the combination to increase the response rate and activity of the checkpoint inhibitor.

TARGETED ONCOLOGY: Could you discuss how these data panned out?

Pujade-Lauraine:This was a very large trial of 560 patients with refractory disease to chemotherapy. There was clinical activity, but the clinical activity in an unselected population in this trial was modest with a hazard ratio (HR) of 0.78 for PFS. There was an increased response rate of 13% versus 4%, but that is still quite small. Globally, the trial was negative.

We tried to look deeper to find out if there were any patients that could benefit more from the combination than from chemotherapy alone. We found that the expression of PD-L1 could perhaps predict clinical activity because in the PD-L1 subgroup, there was an HR of 0.65 for PFS and 0.72 for OS. While this subgroup was prespecified but not preplanned, it is only exploratory.

Another exploratory subgroup is the patients who are primarily resistant, meaning you give chemotherapy and they do not respond. This is the worst population that do not respond to the combination of a PLD and nivolumab, so the combination was not better. For those who had responded, then relapsed and became resistant, those patients seem to benefit more from the combination.

Globally, I would say this is a negative trial. However, it has some track for the future. It is the first step in the long story for the future of immunotherapy in ovarian cancer.

TARGETED ONCOLOGY: What does this mean for JAVELIN program?

Pujade-Lauraine:The JABELIN program is not limited to patients with resistant disease, but it also includes patients in the first-line. That is the JAVELIN 100 study. We know from the press that this trial has been stopped for future study, suggesting again that the hope of nivolumab in the first-line is a bit disappointing. I don’t think the JAVELIN program will develop further in the frontline, but the idea is that we would like to go deeper in this JAVELIN 200 trial to find out more about those patients who could benefit. There is a lot of translational research planned, and we hope to get out some ideas or concepts for a future trial in ovarian cancer.

TARGETED ONCOLOGY: Where might avelumab still have a role in ovarian cancer?

Pujade-Lauraine:It’s not only avelumab; they are all in the PD-L1/PD-1 pathway blockade program. Obviously, if you give this kind of drug to everybody, it won’t work. You have to select, and we know that it is difficult to select patients from all other tumors. The biomarkers are difficult to find, but we now have to combine this kind of checkpoint inhibitor with either an anti-VGEF, which is very important, or a PARP inhibitor, and we have many clues in favor of this combination. Perhaps with other immunotherapy drugs, we can target other immunosuppressive pathways in ovarian cancer.

TARGETED ONCOLOGY: What did we see in the biomarker analysis?

Pujade-Lauraine:The biomarker analysis in JAVELIN 200 is exploratory, which was run in more than 500 patients. This is very large in this disease. The cutoff was those patients who had at least 1% of tumor cells expressing PD-L1 or more than 5% of immune cells expressing PD-L1 within the tumor were considered as positive. It’s a specific cutoff, and it is exploratory. It has to be validated, but it is a very interesting track for the future.

TARGETED ONCOLOGY: What will be the role of immunotherapy in ovarian cancer?

Pujade-Lauraine:We started with irrational hope and enthusiasm for immunotherapy in ovarian cancer. With that, we now have 2 negative trials, and we have irrational despair about immunotherapy. Science is going step by step. It is a learning curve, but the JAVELIN 200 is the first step. We have learned a lot from this trial to [help] in our next future trials.

Reference:

Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on Avelumab in Platinum-Resistant/Refractory Ovarian Cancer [news release]. Darmstadt, Germany: Merck KGaA and Pfizer, Inc; November 19, 2018. https://bit.ly/2PGGzPB. Accessed January 15, 2020.