Expert Discusses Pembrolizumab Plus Rituximab in Follicular Lymphoma

Loretta J. Nastoupil, MD

Pembrolizumab (Keytruda) in combination with rituximab (Rituxan) has shown high response rates in patients with relapsed follicular lymphoma, according to findings from an open label phase II trial.

Twenty patients who received the combination were evaluable for efficacy and 30 were evaluable for safety, with a median follow-up of 8.2 months. The primary endpoint was overall response rate (ORR).

“Our study met our primary endpoint, suggesting the combination is synergistic,” lead investigator Loretta Nastoupil, MD, said in an interview with OncLive during the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland. “We didn't see any additive toxicity so the study continues to enroll.”

OncLive: Can you provide an overview of the study?

Nastoupil, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the positive interim analysis and shared her thoughts on areas of future investigation for patients with relapsed follicular lymphoma.Nastoupil: What we are presenting here at the 2017 Lugano International Conference for Malignant Lymphoma was a single institution phase II study investigating rituximab in combination with pembrolizumab in patients with relapsed follicular lymphoma.

It is important to note that there were patients who were rituximab-sensitive, which was defined by a patient achieving at least a partial response and maintaining that response for at least 6 months during prior rituximab-containing therapy. This was a relapsed population and most of the patients have had a median of 2 prior lines of therapy.

The study’s schema was essentially a phase II open label. Patients received 375 mg of rituximab on days 1, 8, 15, and 22 of cycle 1. They also received pembrolizumab starting on day 2 every 3 weeks for a total of 16 doses. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety.

We’re presenting the interim results based on our preplanned analysis looking at 20 evaluable patients for efficacy and 30 evaluable patients for safety. It is important to note that the ORR was 65%, but the majority of these patients had achieved a complete response and the responses appear to be quite durable, albeit with 8 months of follow-up.

What are your next steps based on these results?

Is pembrolizumab being evaluated in combination with any other agents?

We have not reached our median [PFS or OS] endpoints due to the short follow-up. We have observed no deaths. In regard to safety, we have also observed no grade 4 adverse events (AEs) and the observed grade 3 AEs were very infrequent. The immune-mediated AEs were infrequent, mostly grade 1 or 2. We did remove 4 subjects from the study due to recurrent grade 2 immune-mediated AEs, including 2 patients for diarrhea, 1 patient for rash, and 1 patient for pneumonitis. Our study met our primary endpoint, suggesting the combination is synergistic. We didn’t see any additive toxicity so the study continues to enroll. We are following the additional patients because we have enrolled 30 patients for their efficacy and safety. We're also expanding to a refractory population because this was a rituximab-sensitive population. We are adding a cohort of large cell lymphoma with the addition of lenalidomide (Revlimid). Across different histologies, if you look at single-agent activity of PD-1 antibodies in follicular lymphoma or large cell lymphoma, they are not as good as one would hope. Therefore, combinations seem to be the answer, particularly for these lymphoma subtypes, as opposed to Hodgkin lymphoma, where single-agent activity is quite favorable.

What outstanding questions you would like to see addressed?

In follicular lymphoma, we’ve done combinations with CD20. In large cell lymphoma, we are looking at combinations with CD20 as well as lenalidomide. In other histologies, such as multiple myeloma, there are triplet combination studies that are ongoing.I think, particularly in follicular lymphoma, there is the lack of biomarkers to help drive treatment decisions. It's somewhat surprising that we see such high response rates with the PD-1 antibody in a tumor that has not been known to have a high expression of PD-L1.

We have some biomarker work that is ongoing that may interrogate the preexisting immune system as a potential predictor of response. I think we need further studies to identify which patients are going to respond because in our small series of patients, those that do respond are quite durable. Additionally, the safety profile appears to be quite favorable. [It would be ideal] if we [could] identify patients who are best suited for this approach as opposed to chemoimmunotherapy. Overall, I think we are doing a good job.

What are the most important points from your presentation?

Combinations are still under exploration but outcomes for patients with lymphoma continue to improve. Where there is still a need is for those patients who relapse early, are double refractory to both CD20 and alkylating agents, or for patients with large cell lymphoma who have relapsed and are not candidates for transplant. It's a single-institution, phase II study with a small number of patients, however the response rates are quite high. The complete response rate is quite notable, particularly with this novel PD-1 antibody, which is gaining attention across multiple tumor histologies. Follicular lymphoma is 1 histology that you may not expect to demonstrate high response rates for the PD-1 antibody.

Is there anything else you would like to mention regarding this presentation?

We think the combination is the reason for the higher response rates, particularly for the complete response rates. Further studies are needed to determine how this will play out in a larger patient population. We are quite excited about the preliminary results from this phase II study examining rituximab in combination with pembrolizumab in relapsed follicular lymphoma. We are equally eager to see how this combination is in terms of safety and efficacy in a higher-risk patient population.

Nastoupil LJ, Westin J, Fowler N, at al. High response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. Hematological Oncology, 35(S2): 120-121. doi:10.1002/hon.2437_108.