Which Combination Immunotherapies to Use, and When? Despite Improved Response Rates, Serious Toxicity Remains a Concern

April 2018 Vol 9, No 4

As single-agent immunotherapies continue to show promising results, the challenge is now to determine which combination regimens with immunotherapies can improve outcomes. According to data presented at ASH 2017, 3 approaches are currently being explored: (1) using immunotherapies to replace nonspecific cytotoxic agents to increase efficacy and reduce toxicity; (2) combining an immunotherapy with a targeted drug for chemotherapy-free regimens; and (3) revitalizing T cells by using checkpoint inhibitors in combination with other immune-mediated agents.

Although preliminary research has shown early success with all 3 approaches, Donna Przepiorka, MD, PhD, Cross-Discipline Team Leader, FDA’s Division of Hematology Products, urged caution in interpreting single-arm clinical trials to avoid unpredictable and potentially fatal toxicities. According to Dr Przepiorka, lessons learned from the era of cytotoxic drugs can still be applied to immunotherapies in combinations today.

“The main rationale from the cytotoxic era is to increase efficacy by combining agents that have different mechanisms and nonoverlapping toxicities. The question is whether we can replace nonspecific cytotoxic agents with a specific, more effective immunotherapeutic,” she emphasized.

Brentuximab Vedotin plus Standard of Care?

One such immunotherapy is brentuximab vedotin (Adcetris), which consists of an antibody drug conjugate linked to monomethyl auristatin E. In a single-arm trial of brentuximab vedotin monotherapy for patients with relapsed or refractory Hodgkin lymphoma, 73% of patients achieved a complete response (CR) plus partial response, with modest toxicity.

Although this response rate is “substantial,” said Dr Przepiorka, the investigators wanted to know whether this drug could be added to the standard-of-care chemotherapy regimen known as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or if it should replace bleomycin in this regimen.

In the ECHELON-1 study of 1334 patients with advanced-stage Hodgkin lymphoma, patients were randomized to the replacement regimen of brentuximab vedotin plus AVD or to the standard-of-care ABVD regimen. The replacement regimen showed superior results, with a hazard ratio (HR) of 0.77.

Nevertheless, despite the modest benefit in progression-free survival (PFS), different toxicity profiles for these combinations should be taken into account, Dr Przepiorka noted.

“Less pulmonary toxicity was clearly confirmed in this study, with less than 1% of patients having a grade 3 or higher pulmonary event, but we still need to be vigilant for this toxicity,” said Dr Przepiorka. “Moreover, although there is less pulmonary toxicity in the BV [brentuximab vedotin] arm, there is far more neurotoxicity, as well as more febrile neutropenia and infection. Safe use of this regimen appears to require additional use of filgrastim prophylaxis,” she added.

Blinatumomab plus Standard Chemotherapy?

The efficacy of blinatumomab (Blincyto), a first-in-class immunotherapy known as a T-cell engager, was demonstrated in the randomized clinical trial TOWER, which compared monotherapy with blinatumomab versus standard chemotherapy for patients with relapsed or refractory Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL).

The CR rate for the blinatumomab arm was nearly double that of conventional chemotherapy, and survival analysis showed evident superiority for blinatumomab, with an HR of 0.71. Although the safety profile of blinatumomab differs from that of the usual cytotoxic chemotherapies used for ALL, there is concern that ALL drugs would counteract the effects of blinatumomab. However, if blinatumomab were combined with a targeted agent that spared T cells, Dr Przepiorka explained, this may be less of a problem.

Assi and colleagues looked at the efficacy of blinatumo­mab plus a tyrosine kinase inhibitor (TKI) in patients with Ph-positive ALL. Although the study included a small number of patients, the updated data showed a 54% CR rate, said Dr Przepiorka, and currently 2 single-arm trials of chemotherapy-free blinatumomab plus a TKI are ongoing.

“It’s encouraging to think that this may open the door to chemotherapy-free treatment of ALL by using a T-cell engager with targeted therapy,” Dr Przepiorka said. “However, only a randomized trial with long-term follow-up will be able to tell us whether this combination is effective,” she added.

Immunomodulatory Drug plus Checkpoint Inhibitor?

In the meantime, researchers are still trying to understand why not all patients respond to this treatment. One possible explanation for this failure, said Dr Przepiorka, is T-cell exhaustion, which occurs when T cells are persistently stimulated by antigens in patients with chronic infections and in those with cancer.

Although checkpoint inhibitors have been proposed as a way to revitalize exhausted effector T cells, response rates for checkpoint inhibitors in hematologic malignancies are generally low. One possible solution is to use an immunomodulatory drug (IMiD) to enhance the effect of the checkpoint inhibitor.

In a single-arm, phase 2 clinical trial, Badros and colleagues used pembrolizumab (Keytruda) in combination with pomalidomide (Pomalyst) and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. In 48 patients treated, the overall response rate was 60%, and the median PFS was 17.4 months. However, 42% of patients had grade ≥3 adverse events, and 13% had pneumonitis; still, only 11% discontinued treatment because of toxicity.

“It is clearly difficult to assess the benefits of this combination in a single-arm setting,” said Dr Przepiorka, adding that 2 studies with pembrolizumab, KEYNOTE-183 and KEYNOTE-185, were terminated early because of increased deaths in the pembrolizumab arms, with a 61% increase in the relative risk of death in the pembrolizumab arm in patients with relapsed or refractory disease, and a doubling of the risk of death in patients with newly diagnosed disease.

“We’ve learned from this experience that single-arm trials of combinations can be difficult to interpret, so we should consider randomized trials, even in the early stages. Moreover, we still do not understand the biological reasons for increased toxicity in the KEYNOTE studies,” said Dr Przepiorka.

“Additional randomized trials with other IMiDs and checkpoint inhibitors are ongoing, with frequent assessments of safety, but until we understand why this toxicity occurred, all such trials are being watched closely,” she concluded.

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Last modified: November 5, 2020

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