	Director, Georgetown Lombardi Comprehensive Cancer Center Chairman, Department of Oncology Francis L. and Charlotte G. Gragnani Chair Georgetown University Medical Center Washington, DC

	Division of Hematology and Oncology Department of Medicine University of Virginia School of Medicine Charlottesville, VA

	Chief, Translational Research Immunotherapy Director, Melanoma Program The Angeles Clinic and Research Institute Santa Monica, CA

	Ensign Professor of Medicine (Medical Oncology) Chief, Medical Oncology Associate Director, Translational Research Yale Cancer Center Yale School of Medicine New Haven, CT

	Professor, Medicine and Thoracic Surgery Director, Lung Cancer Section UPMC Lung Cancer Center of Excellence Pittsburg, PA

As varying immunotherapy options become available for different types of cancers, researchers will have to take the next steps in clinical studies and in practice before the growing excitement over emerging agents can truly be translated into beneficial new therapies for patients, according to experts who participated in a recent OncLive Peer Exchange program.

Leading researchers discussed a broad range of considerations that have become evident in the development of immunomodulatory therapies during a recent Peer Exchange session entitled “Antibody- Based Cancer Immunotherapy,” that focused, in particular, on agents that target programmed cell death-1 (PD-1) and its ligand, PD-L1.

: Tactics for Improving Rituximab Regimens Vary With Subtype

Louis M. Weiner, MD, who served as moderator of the discussion, said he believes that immunotherapy will work on every tumor type, but that complex scientific questions about which patients will benefit must be investigated. He stressed that in the future, researchers and clinicians will have to recognize that the heterogeneity of cancers, “… is going to become a critical determinant of who responds, how well they respond, and if they do relapse, how they relapse. And the challenge before us as clinical investigators and before our scientific colleagues is going to be to dive down deeply and understand what some of those mechanisms are and how the selection pressures influence these processes. And I think that preclinical models can help us with this, but…we’re also going to have to figure out how to do clinical trials that allow us to interrogate some of these concepts in a prospective way as well. So it’s very challenging but really quite exciting, I think.”

Although activating the immune system as a therapeutic approach in cancer has long been a cooperative goal between immunology and oncology, the FDA’s approval of the anti-CTLA4 antibody ipilimumab for melanoma in 2011 acted as a springboard for the current research focus. Immune checkpoint blockade therapy engages antibodies targeting T-cell inhibitory pathways, such as CTLA-4 and PD-1/ PD-L1, and is emerging as an important strategy in cancer immunotherapy.

Demonstrated efficacy and safety of the antibody- mediated PD-1 blockade strategy in the setting of melanoma led to the FDA approval of pembrolizumab in September 2014 and nivolumab in December 2014 for the treatment of metastatic melanoma. These and other PD-1/PD-L1-targeted agents, as well as additional immune checkpoint modulators, are under investigation as treatment in both solid tumor and hematologic cancers.1

With the approval of these two additional immune checkpoint agents, the treatment of melanoma continues to advance. Researchers are now looking at the most effective use of these agents as either monotherapy and in combination with other immunotherapy agents and targeted therapies.

Tolerability and the development of predictive biomarkers that guide treatment selection will determine the future role of checkpoint inhibitors in melanoma, said Omid Hamid, MD.

Past trials have highlighted the toxicity involved in the combination of BRAF and CTLA-4 therapies, particularly ALT/AST increase and bowel perforation. Additionally, side effects were a concern with the combination of nivolumab and ipilimumab. However, the combination of ipilimumab and talimogene laherparepvec (T-VEC), an oncolytic immunotherapy virus, appeared to be well tolerated, Hamid added.

Many of the studies that are needed to provide clues on combinations and biomarkers are already accruing patients, noted Hamid. Additionally, drugs that have shown promise in the metastatic setting are being explored in the adjuvant space and in combinations.

Roy S. Herbst, MD, PhD, suggested that another question that needs to be asked is why aren’t patients responding to therapy? To answer this, more research is needed into biomarkers, said Weiner. PD-L1 levels are being examined as a potential biomarker but PD-L1 status by itself is unlikely to be the only biomarker that is needed, particularly since patients who tested PD-L1 negative in clinical trials still responded to treatment. To answer this question, studies examining MPDL3280A, a PD-L1 inhibitor, are looking at markers of T-cell activation, changes in PD-L1 staining, and gene arrays, noted Hamid.

Potential Change in Metastatic Bladder Cancer

According to Robert Dreicer, MD, MS, (formerly of the Cleveland Clinic), findings from a phase 1B trial with MPDL3280A in metastatic urothelial bladder cancer “… provides us not just a little bit of an inkling, but a really amazing potential transformation in the management of the disease.”

In June 2014, the FDA granted MPDL3280A breakthrough therapy designation in metastatic bladder cancer. This designation was based on preliminary results from the phase I trial of 68 patients with metastatic urothelial bladder cancer who received prior chemotherapy. The objective response rate with MPDL3280A was 43% in PD-L1 positive patients (IHC 2/3). At the time of the data cut-off, 94% of patients had ongoing responses.

The most common all-grade adverse events were decreased appetite (12%), fatigue (12%), and nausea (12%).2 Several additional trials are continuing to examine MPDL3280A in patients with urothelial bladder cancer. A large phase II study of MPDL3280A is currently enrolling patients with metastatic urothelial bladder cancer. The study will have two cohorts, one for treatment-naïve patients and the other for patients who have been treated (NCT02108652). Another open-label, randomized, phase III trial will compare the efficacy and safety of MPDL3280A with chemotherapy in patients who progressed during or following a platinum-containing regimen (NCT02302807).

While great strides have been made in the treatment of non—small cell lung cancer (NSCLC), using targeted therapy focused on oncogenic drivers, Mark A. Socinski, MD, stressed that “…we need to think out of the box. And I think integrating immunotherapeutic approaches in that setting is an area that should be of intense interest.”

In October 2014, this out-of-the-box thinking became a reality with the FDA granting pembrolizumab a breakthrough therapy designation for the treatment of patients with NSCLC who are EGFR mutation- or ALK rearrangement-negative and whose disease has progressed on or following platinum-based chemotherapy. This designation was based on the interim results of the phase I KEYNOTE-001 study. Ongoing studies of pembrolizumab in NSCLC include the phase II/III KEYNOTE-010 study (NCT01905657), which seeks to evaluate two doses of the drug versus docetaxel in patients who have progressed after platinum-containing therapy, and the phase III KEYNOTE-024 study (NCT02142738), which is comparing pembrolizumab with platinum-based chemotherapies in metastatic disease.

MPDL3280A is under investigation in several trials including the single-arm phase II BIRCH (NCT02031458) study in patients with PD-L1—positive locally advanced or metastatic NSCLC and the phase III OAK study (NCT02008227) comparing the agent with docetaxel in patients who have failed platinum therapy.

For nivolumab, clinical trials include the phase III CheckMate 057 study (NCT01673867), which compares the agent with docetaxel in previously treated metastatic non-squamous NSCLC, and the phase III CheckMate 026 study (NCT02041533) of nivolumab versus investigator’s choice chemotherapy in stage 4 or recurrent PD-L1—positive NSCLC.

The use of immune checkpoint therapy in kidney cancer is more challenging. There are several phase I trials being conducted examining PD-1/PD-L1 agents as monotherapy and in combination in patients with advanced or metastatic renal cell cancer. One of the larger studies is the phase II CheckMate-010 (NCT01354431) dose-ranging trial of nivolumab as a single agent in patients with advanced or metastatic renal cell carcinoma. While the overall response rate ranged from 20% to 22%, with a progression-free survival of about 4 months, there may be patients who achieve durable disease control with therapy with longer follow-up.3

Hamid noted that “In renal cell carcinoma, IL-2, high dose IL-2, has been a standard that somehow has been replaced because of the ease of giving TKIs [tyrosine kinase inhibitors]. Where does high-dose IL-2 stand in its ability to be replaced by these checkpoint inhibitors or in its ability to be the comparator for these checkpoint inhibitors?” This question is an important one that researchers in renal cell carcinoma must contemplate.

Although the immune checkpoint blockade strategy has already shown efficacy in many solid tumors, PD-1/PD-L1 inhibition is also being investigated in hematologic malignancies. During the past year, data from two smaller studies into the anti-PD-1 monoclonal antibody pidilizumab were published. One study demonstrated that the combination of pidilizumab plus rituximab was well tolerated and effective in patients with relapsed follicular lymphoma,4 while the other found that using pidilizumab after autologous hematopoietic stem-cell transplantation may represent a promising therapeutic strategy in diffuse large B-cell lymphoma.5

More recently, researchers highlighted reports from the phase 1B KEYNOTE-013 study,6 which included patients with relapsed/refractory classical Hodgkin Lymphoma (cHL) who had progressed on or after treatment with brentuximab vedotin after failure of autologous stem-cell transplant or who were transplant-ineligible. Of the 29 evaluable patients with cHL who received pembrolizumab, six (21%) experienced complete remission while 13 (45%) achieved a partial remission. Among the remaining participants, six patients (21%) had stable disease while four (14%) experienced progressive disease.

			Stewart R, Hammond SA , Oberst M, Wilkinson RW. The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer. J Immunother Cancer. 2014;2:29.

			Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). Presented at: the 50th Annual Meeting of the American Society of Clinical Oncology, May 31, 2014. J Clin Oncol 32:5s. Abstract 5011.

			Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32:52(suppl;abstr 5009).

			Westin JR, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial [published online December 11, 2013]. Lancet Oncol. 2014;15(1):69-77.

			A rmand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. [published online October 14, 2013]. J Clin Oncol. 2013;31(33):4199-4206.

			Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 Blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Presented at: 56th American Society of Hematology Annual Meeting; December

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As varying immunotherapy options become available for different types of cancers, researchers will have to take the next steps in clinical studies and in practice before the growing excitement over emerging agents can truly be translated into beneficial new therapies for patients.

By Sara L. Thier, PhD, MPH

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