ASCO Preview: Elotuzumab’s ‘Double Whammy’ Mechanism Hits Hard In Myeloma
This article was originally published in The Pink Sheet Daily
Executive Summary
Lead investigator for Bristol/AbbVie’s Phase III ELOQUENT trial of elotuzumab in myeloma says PFS curves are reminiscent of PD-1 inhibitors, expects overall survival benefit to be evident soon.
Positive results from the Phase III ELOQUENT-2 study of Bristol-Myers Squibb Co./AbbVie Inc.’s elotuzumab in relapsed/refractory myeloma highlight the drug’s immunotherapeutic effect and suggest an overall survival improvement could be coming soon, according to the lead investigator.
Originally developed by PDL BioPharma Inc., elotuzumab is one of a range of drugs Bristol has been developing as follow-ons to its show-stopping checkpoint immunotherapies – the CTLA-4 inhibitor Yervoy and the PD-1 inhibitor Opdivo (Also see "Follow The Leader: Bristol Aims To Build On Head Start In Cancer Immunotherapy" - Pink Sheet, 24 Jun, 2013.).
Elotuzumab Quick Facts
- First-in-class elotuzumab attaches to a cell surface protein called SLAMF7 that is found on myeloma cells and on natural killer cells, so it can target the malignant cells and spur an immune response
- Bristol sealed development and commercialization deal with originator PDL in August 2008
- AbbVie acquired Facet (new name for PDL) in March 2010, became Bristol’s co-pilot on elotuzumab
The ELOQUENT-2 study tested elotuzumab as an add-on to standard treatment with Celgene Corp.’s immunomodulator Revlimid (lenalidomide) and the steroid dexamethasone in multiple myeloma patients who had previously had one to three prior therapies. A second Phase III study called ELOQUENT-1 is ongoing in first-line myeloma, with results expected in 2016.
Bristol and AbbVie declined to comment on the registration timeline for the agent, which has “breakthrough therapy” status with FDA for use in relapsed myeloma as part of a three-drug combination with Revlimid and dexamethasone.
The drug met the ELOQUENT-2 study’s co-primary endpoints related to progression-free survival and objective response rate in an interim analysis; the five-month benefit for PFS was highlighted during the American Society of Clinical Oncology’s annual meeting preview briefing on May 13, coinciding with the release of abstracts for the May 29-June 2 meeting in Chicago.
ELOQUENT-2 Results
Summary: Elotuzumab with Revlimid and dexamethasone vs. Rev/dex alone in 646 patients with early relapsed/refractory myeloma (one to three prior therapies)
Co-primary endpoints: Progression-free survival and objective response rate
Key efficacy results: Significant benefit for both endpoints after 24 months. PFS was 19.4 months in treatment group vs. 14.9 months for control. ORR was 79% vs. 66% for control. Benefit seen in patients with high-risk genetic features – del(17p) and t[4;14].
Overall survival: Data could take another six months to mature, but signs are positive.
Safety: Limited safety data released as of May 13. Drug said to be well-tolerated with no deterioration in quality of life. Mild infusion reactions reported in 10% of patients at start of treatment.
In addition to securing a spot in the ASCO preview briefing, Bristol is also the only big pharma with a place in the coveted plenary session of the annual meeting. The plenary session – slated for May 31 – includes eagerly awaited data from Bristol’s Phase III CheckMate 067 study testing its checkpoint inhibitor combination –Yervoy (ipilimumab) with Opdivo (nivolumab) – in first-line advanced melanoma.
The Double Whammy
Elotuzumab was described in the press briefing as an inhibitor of the cell surface protein SLAMF7 (also known as CS-1), which is found on myeloma cells and also on natural killer cells in the immune system. The drug works differently in these settings, however. In myeloma, it attacks malignant cells but in the immune system, it revs up natural killer cells to attack myeloma cells.
During the May 13 briefing, ELOQUENT-2 lead investigator Sagar Lonial stressed the value of the drug’s “double whammy” approach, especially the immune-mediated effects.
In the trial, PFS continued to improve after two years of follow-up – the difference between the treatment group and control grew over time. Lonial likened the durable responses to the effects of PD-1 inhibitors.
“This idea of the maintenance of benefit over time really speaks to the power of an immune-mediated based approach when we treat cancer,” Lonial, a professor of hematology at Emory University, said.
Lonial also noted that the survival analysis is immature at this time – it probably needs another six months – but the signs are “very encouraging.”
A strong benefit could offset the additional costs of adding a third drug to a two-drug regimen, he said.
“If we are increasing or potentially even curing a subset of patients through the addition of an immune-based approach in combination with lenalidomide, that in many ways I think changes the game,” he said.
In addition to the ELOQUENT-2 data, sponsors will be releasing positive results from a Phase II study of elotuzumab with Takeda Pharmaceutical Co. Ltd.’s proteasome inhibitor Velcade (bortezomib) and dexamethasone in relapsed/refractory myeloma at the ASCO meeting (abstract #8573).
The ELOQUENT-2 data will be presented alongside the Phase III ENDEAVOR results for Amgen Inc.’s proteasome inhibitor Kyprolis (carfilzomib) in combination with Velcade and dexamethasone for relapsed/refractory myeloma, as well as late-breaking data for Johnson & Johnson/Genmab AS’s anti-CD38 monoclonal antibody daratumumab as a last-line monotherapy option in heavily pretreated patients.