by Stephanie Hawthorne; co-authored by Elizabeth Clarke
The field of immunotherapy in oncology has exploded in the last few years, particularly in the case of immune checkpoint inhibitors, which block the immune system’s “brakes” by inhibiting either CTLA-4, PD-L1, PD-L2 or PD-1 (although inhibitors of other immune checkpoint molecules are also in early stages of development). Since the original FDA approval of Yervoy® (ipilimumab, BMS/Ono Pharmaceuticals), development of this field has accelerated rapidly. Currently, two PD-1 inhibitors are marketed ‒ Opdivo®(nivolumab, BMS/Ono Pharmaceuticals) in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) and Keytruda® (pembrolizumab, Merck & Co.) in melanoma and NSCLC ‒ and there is considerable Phase III development of these and several PD-L1 inhibitors in other solid tumor and hematologic indications, making the market for these highly efficacious agents increasingly crowded.
At the 57th American Society of Hematology (ASH) Annual Meeting in Orlando this week, Merck reported the results from both a single-arm Phase I and a single-arm Phase II trial, evaluating the efficacy and safety of two different combinations of Keytruda in relapsed/refractory multiple myeloma. There is a strong rationale for targeting the PD-L1/PD-1 axis in multiple myeloma, as PD-L1 expression is naturally high across all stages of the disease, and T-cell expression of the molecule is increased in relapsed/refractory patients.1
First, an open-label, Phase I, multicenter, non-randomized, dose-escalation trial (NCT02036502, KEYNOTE-023) evaluated the safety, tolerability and efficacy of Keytruda plus Revlimid® (lenalidomide, Celgene) and low-dose dexamethasone (RevDex) in the relapsed/refractory setting (median of four prior lines of treatment). With a median follow-up of 296 days, the objective response rate (ORR) was 76% (nine of the 17 patients achieved a partial response and four of the 17 achieved a very good partial response). In addition, a whopping 94% of patients experienced reduction in M protein or free light chains (which are biomarkers of active disease) with a median of 50% reduction in levels. The median duration of response was 9.6 months and the median time to first response was rapid, at 1.2 months. The combination was well-tolerated, with only three patients experiencing a dose-limiting toxicity (DLT): neutropenia (Grade 3/4), infectious pneumonia (Grade 3) and tumor lysis syndrome (Grade 3) with hyperuricemia (Grade 4). Based upon these data, the maximum tolerated dose/maximum administered dose (MTD/MAD) was established as Keytruda 200 mg fixed dose in combination with standard dose RevDex (Revlimid 25 mg and low-dose dexamethasone 40 mg). What is so remarkable about the “promising preliminary activity” observed with Keytruda in this study, as aptly stated by the discussant Dr. Jesus San Miguel, is that many of the patients included in the trial were refractory to Revlimid.2 Indeed, the preliminary results of KEYNOTE-023 demonstrate that PD-1 blockade with Keytruda in combination with RevDex is associated with promising disease-targeted activity and a tolerable safety profile in heavily pretreated relapsed/refractory multiple myeloma patients.
In addition to the Phase I results, interim data were reported from an ongoing single-arm, Phase II trial (NCT02289222, conducted at the University of Maryland and partially sponsored by Merck) evaluating the efficacy and safety of Keytruda in combination with Pomalyst® (pomalidomide, Celgene) and dexamethasone in relapsed/refractory patients. In the study, relapsed/refractory multiple myeloma patients (median of three prior lines of treatment) received 28-day cycles of Keytruda (200 mg IV every two weeks) plus Pomalyst (4 mg daily x 21 days) and dexamethasone (40 mg weekly). Hematologic toxicities (Grade 3 or higher) were neutropenia (29%), lymphopenia (17%) and thrombocytopenia (8%). The most common non-hematologic adverse events included (Grade ≤2; ≥3): fatigue (n=12; 1), constipation (n=10; 0), dyspnea (n=9; 2), itching (n=6; 0), muscle spasms (n=6; 0) and hyperglycemia (n=5; 0). Objective responses were observed in 16 of 27 (60%) evaluable patients, including stringent complete response (n=1), very good partial response (n=4) and partial response (n=11); additionally, eight patients had stable disease. The time to best response (as in KEYNOTE-023) was rapid, with a median value of 2.0 months. Data on survival and progression-free survival (PFS) is very preliminary (only 7.4 months’ follow-up), but looking at the Kaplan-Meier curves suggests the six-month overall survival exceeds 80% and six-month PFS exceeds 60%.3 Overall, the data demonstrate that Keytruda in combination with Pomalyst and dexamethasone has favorable therapeutic activity and an acceptable safety profile in heavily pretreated multiple myeloma and thus may represent an efficacious combination regimen for this indication (similar to the results seen above with Keytruda + RevDex).
Presumably based on early readout of these data, Merck initiated two Phase III trials of Keytruda in multiple myeloma in October 2015. At the time, the data prompting those trial initiations was unknown, so the readout of these two studies at ASH sheds light on the rationale for their initiation. KEYNOTE-183 (NCT02576977) will randomize patients to treatment with Pomalyst/dexamethasone with or without Keytruda as third-line or later treatment (prior therapy with an immunomodulatory and proteasome inhibitor is required). KEYNOTE-185 (NCT02579863) will randomize newly diagnosed patients to treatment with Revlimid/dexamethasone with or without Keytruda. In addition to Keytruda, the checkpoint inhibitors Opdivo (with or without lirilumab; NCT01592370), atezolizumab (with or without Revlimid; NCT02431208), and durvalumab (with or without Pomalyst; NCT02616640) are being evaluated in this space (Phase I trials), putting Keytruda well ahead of the competition in this indication. However, the market in relapsed/refractory multiple myeloma is already quite crowded. In November 2015 alone, this space has seen three new approvals ‒ the anti-CD38 antibody Darzalex™ (daratumumab, Genmab), the next-generation proteasome inhibitor Ninlaro® (ixazomib, Millennium/Takeda) and the SLAMF7-directed antibody Empliciti™ (elotuzumab, BMS/AbbVie) ‒ in addition to the numerous other agents that have been previously approved for this disease (Kyprolis® (carfilzomib, Amgen), Farydak® (panobinostat, Novartis), Pomalyst, Revlimid, and Velcade® (bortezomib, Takeda)).
Is there room in the relapsed/refractory space for immune checkpoint inhibitors? The early-stage Keytruda trials described here evaluate the agent in the context of established backbone therapies (e.g., RevDex), which should bolster the efficacy of the therapy and more easily incorporate it into the treatment paradigm. By initiating two Phase III trials at nearly identical times, Merck is positioning Keytruda well for incorporation into practice. Ultimately, given what we know about the efficacy of checkpoint inhibitors in other tumor types, the KEYNOTE-185 trial in first-line may be where Keytruda ultimately fits into practice; however, that trial will likely take longer to read out, which positions the KEYNOTE-183 trial as the first opportunity for Keytruda to enter the myeloma market in the relapsed/refractory setting. This is the first Phase III trial seeking to add a novel targeted agent onto a Pomalyst/dexamethasone backbone regimen, so this strategy is diving into unknown waters but comes with the advantage of distinguishing Keytruda from the other targeted agents seeking development in combination with doublet regimens. If Keytruda ends up being as successful in multiple myeloma as it is in a host of other tumor types, it could present a fair challenge to these already-existing therapies.
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