Emergence Of New Myeloma Drugs, And Combinations, Raises Red Flag On Costs

The rise of a range of new therapies and protocols for multiple myeloma, including potent three-drug combination regimens, is stirring concerns about costs and demand for better biomarkers to direct treatment.

The American Cancer Society describes multiple myeloma as a “relatively uncommon” cancer, with an estimated 26,850 new cases and 11,240 deaths in the U.S. in 2015. Yet the disease has been a fertile area for drug development.

The leading drugs on the market are Takeda Pharmaceutical Co. Ltd.’s proteasome inhibitor Velcade (bortezomib) and Celgene Corp.’s immunomodulator Revlimid (lenalidomide), which have had a dramatic, positive impact on overall survival since 2000. Celgene’s immunomodulator Pomalyst (pomalidomide) and Amgen Inc.’s proteasome inhibitor Kyprolis (carfilzomib) have both been approved for use in relapsed patients, and sponsors are trying to capture share from the older drugs and move to earlier lines of therapy.

Amgen is positioning Kyprolis as a proteasome inhibitor with less toxicity than Velcade as it tries to move the drug to front-line therapy. As DataMonitor analysts pointed out in a white paper at the recent American Society of Clinical Oncology annual meeting, Kyprolis is positioned to “emerge as a major disruptive force in the multiple myeloma market,” but new therapies may present challenges in the future (Also see "Analysts Pick Top 10 ASCO Abstracts To Watch" - Pink Sheet, 18 May, 2015.). According to the BioMedTracker database, seven candidates are in Phase III or filed for the disease, and about a dozen are in Phase II.

But with many of those trials looking at multi-drug combinations and/or testing established regimens at higher doses, the changes that are occurring or are expected in the treatment landscape are drawing scrutiny about high costs. “Financial toxicity” and discussions about value were a major theme at ASCO, and the organization on June 22 released its much anticipated framework for assessing the value of cancer therapies (Also see "ASCO Value Framework Presents ‘Net Health Benefit’ Score For Drugs" - Pink Sheet, 22 Jun, 2015.).

Costs Set To Escalate

Amgen pitted Kyprolis directly against Velcade in the head-to-head ENDEAVOR trial, presented June 2 at ASCO. The 929-patient Phase III trial, in patients who had received one to three prior therapies, showed a statistically significant doubling of progression-free survival (18.7 months vs. 9.4 months) in patients on Kyprolis with dexamethasone compared to Velcade/dexamethasone.

Overall survival data are immature, and “time will tell if this difference persists,” UCSF’s Jeffrey Wolf said in discussing the results, but the objective response rate was higher in the Kyprolis treatment arm.

Cardiovascular events were higher with Kyprolis as expected, but peripheral neuropathy was lower compared to the Velcade arm, also not a surprising outcome given that one-fifth of patients took Velcade intravenously, Wolf said.

However, Wolf also noted that the dose used in ENDEAVOR was 56 mg/m², twice the approved dose, which he expects will double the cost of carfilzomib (see table). This is likely the optimal dose for the drug, he added. Wholesale acquisition costs provide a means of comparison, but do not account for discounts. Also, in addition to the costs of the actual drug, there are expenses for infusions, where necessary, and managing toxicities.

Velcade loses exclusivity in 2017, which in theory could mean lower prices, but it’s unclear if the drug’s market will be attractive enough to encourage the entrance of biosimilar manufacturers.

Wolf also highlighted results from Amgen’s ASPIRE study of relapsed myeloma, in which patients who took the triple combination of Kyprolis (approved dose) with Revlimid and dexamethasone had a median PFS of 26 months, with a median duration of treatment of 88 weeks. Wolf described this as a “remarkable achievement” that sets a new standard for PFS.

Longer treatment times and stacked therapies are likely to draw attention of insurance companies, commented Alex Bastian, VP of market access at the consultancy Gfk. The result could be greater use of treatment pathways for myeloma; evidence-based pathways to guide treatment are an increasingly common means of standardizing quality (and cost) for cancer care.

“How the payers view and respond to these will become increasingly important in the coming year or two,” he said via email after ASCO.

Cost is also an issue for a triple combo that incorporates Bristol-Myers Squibb Co.’s Phase III elotuzumab, presented at ASCO alongside the ENDEAVOR results (Also see "ASCO Preview: Elotuzumab’s ‘Double Whammy’ Mechanism Hits Hard In Myeloma" - Pink Sheet, 13 May, 2015.).

The first-in-class drug 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. The drug was added to Revlimid and dexamethasone in the ELOQUENT-2 study, and improved PFS by 4.5 months compared to dexamethasone alone in relapsed myeloma. The PFS benefit is smaller than what has been seen in trials of other drugs in a similar setting, but Wolf noted the extraordinarily high percent of high-risk patients relative to other studies. Overall survival data are immature, but investigators see a trend in the right direction with durable responses and a tail on the PFS curve.

The overall survival results will be important, BioMedTracker analysts noted, as the PFS benefit – while in-line with recently approved therapies – was “somewhat modest” compared to the 8.7-month PFS benefit seen in the ASPIRE trial when Kyprolis was added to the same Revlimid/dexamethasone control.

Elotuzumab was impressive in terms of the side-effect profile; toxicity rates were similar for elotuzumab plus Revlimid and dexamethasone versus lenalidomide/dexamethasone alone, suggesting elotuzumab has minimal added toxicity.

Wolf described elotuzumab as “an easy drug to add to other combinations,” based on the toxicity profile, and noted it could have a role in the front-line setting perhaps as an add-on to Kyprolis/Revlimid/dexamethasone. The clinician added that “it will be interesting to see how it fares against the coming anti-CD38 antibodies.”

Janssen Pharmaceutical Cos./Genmab AS initiated a rolling submission for their anti-CD38 daratumumab in early June, for treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent (Also see "J&J’s Oncology Strategy: Aim For Next-Gen Immuno-Oncology, More M&A" - Pink Sheet, 1 Jun, 2015.). Other members of the anti-CD38 class are in earlier stages of development.

Wolf said that the costs of combinations must be weighed against performance. If the PFS or tail in the survival curve is significant enough, the increased cost may be offset and worth it, he said.

But, he noted, “this all presupposes that the costs for these drugs do not come down, and of course we all hope they will.”

If one considers costs and length of progression-free survival, based on cross-trial comparisons, the Kyprolis/Revlimid/dexamethasone regimen costs about the same as a double dose of Kyprolis with dexamethasone, Wolf estimated, but is worth more in terms of the cost per progression-free month.

Gfk’s Bastian commented that the entry of immunotherapies in myeloma would also draw payer scrutiny. Leading sponsors of PD-1/PD-L1 inhibitors are now testing their drugs in early-stage combination trials in myeloma. Furthermore, Novartis AG has a Phase I study of its CAR-T therapy CTL019 up and running in myeloma.

“The big question broadly for the field in oncology is what is the best way to incorporate immunotherapeutic approaches with backbone regimens in the diseases where those agents may be relevant, and what’s the best way to combine those or sequence those?” Michael Vasconcelles, global head of Takeda’s oncology therapeutic area unit, said in an interview at the ASCO meeting. “That’s being talked about of course across the spectrum in oncology now.”

Takeda’s current preoccupation, however, is getting a filing ready for its next-generation proteasome inhibitor ixazomib, as part of an all-oral combination with Revlimid with dexamethasone (Also see "Takeda’s Weekly Oral Proteasome Inhibitor Ixazomib Passes First Pivotal Test" - Pink Sheet, 10 Feb, 2015.). The exec contrasted the more convenient oral administration with more complex dosing of the antibodies in development. Takeda is also going to be looking to highlight ixazomib’s toxicity profile. A filing in relapsed myeloma will be submitted by the end of Takeda’s fiscal year: March 2016.

Justifying Top Dollar Pricing

If a combination proves to be curative in the front-line setting, “almost any cost may be acceptable,” Wolf maintained at the ASCO meeting.

However, the clinician also noted the lack of adequate biomarkers, which results in many cases in spending money on therapies that offer little benefit and cause toxicities.

Until clinicians are able to direct treatment more accurately, he said, “we will continue to mix and match these new drugs, looking for the best combinations and, ultimately, a cure for our patients, we hope.”

In another ASCO presentation, Carolinas HealthCare System Oncologist Saad Usmani noted the discrepancies between different types of myeloma and that treatment is still difficult for high-risk patients.

Evaluation of minimal residual disease using flow cytometry or DNA sequencing looks promising to help predict who will respond and who will relapse quickly, but an assay has not been standardized and clinical trials are needed to establish this as a biomarker.

“If we truly believe that complete responses lead to improved outcomes, minimal residual disease would be the logical next step,” Usmani said.

The biomarker issue is challenging, Bastian commented after the meeting, because there “really isn’t much on the near-term horizon to offer hope or a solution” in the marketplace.