Celgene’s withdrawal of a European submission for blockbuster Revlimid (lenalidomide) in front-line/maintenance multiple myeloma and a delay of the FDA filing in that indication has clear implications for reimbursement in Europe, but may have less of a hit in the U.S. where off-label prescribing is covered by insurance companies.

Currently approved for second-line use in multiple myeloma in the U.S. and Europe, Revlimid sales hit $3.2 billion in 2011, up 30% from the previous year. In the U.S. the drug is used off-label in newly diagnosed patients and as a maintenance treatment.

After induction treatment regimens, patients may still have residual disease and using a maintenance therapy until disease progression makes sense clinically as a means of preventing relapse, as long as efficacy is proven and toxicities are acceptable.

Celgene announced June 21 that it decided to withdraw the submission to the Committee for Medicinal Products for Human Use for maintenance in patients who have not progressed following initial treatment of newly diagnosed multiple myeloma with Revlimid, melphalan and prednisone, or as a maintenance therapy after autologous stem cell transplantation.

Furthermore, the company says it is “re-evaluating our Revlimid newly diagnosed submission to FDA” and anticipates submitting an application in 2013.

Emerging options for relapsed myeloma

June 20: ODAC votes overwhelmingly to approve Onyx’ Kyprolis, filed under accelerated approval

June 21: Celgene says pomalidomide accepted for standard review by FDA

Celgene plans to resubmit with more mature survival data, to allow the CHMP to conclude a clear benefit/risk ratio.

“Our own view is we’re probably going to have to look at data every three months, so in the next three to six months we’ll reexamine the opportunity for resubmission,” CEO Robert Hugin explained during a June 21 analyst briefing.

The company considered alternative options – for example, separating induction and maintenance indications, or limiting approval to subsets of patients – but ultimately decided that the best course was to withdraw the filing and wait for the data to mature.

With New Risks, Was Benefit Enough?

The decision was prompted by reports of second primary cancers, including acute myeloid leukemia and myelodysplastic syndromes, in three studies of Revlimid for first-line/maintenance treatment. Two studies – CALGB100104 and IFM-2005-02 – examined the drug after stem cell transplant and the third trial – MM-015 – tested the drug in patients who had not undergone transplant. The results were reported at the American Society of Hematology meeting in 2010 and published in the New England Journal of Medicine May 10, 2012 Also see "Revlimid In Limbo: Market Slams Celgene, Physicians And Payers Take Wait And See Approach" - Pink Sheet, 13 December, 2010..

In the three studies, Revlimid demonstrated impressive efficacy benefits, almost doubling progression-free survival and time to progression, the primary endpoints. But a benefit for overall survival was demonstrated in only one trial and the improvement was modest in that case. The rates of second primary cancers in the studies ranged from 7%-8%, compared to 3%-4% for placebo.

In the process of responding to questions from the CHMP, it became clear that the potential impact of second primary malignancies on survival had become a “principal concern,” Hugin said.

As was the case when malignancies were first reported, the market was quick to punish Celgene; on June 21, the stock was trading at $59.44, down 11.5%.

There were important differences in study design that help explain differing outcomes, according to Philip McCarthy, lead investigator on the CALGB100104 study – the only one of the three studies based in the U.S. and the only one to show a survival benefit. For example, lenalidomide therapy was terminated early in the IFM Group study, making it difficult to see the full benefit of continuous therapy, whereas treatment continued in the other two trials. Geographic differences also played a role in terms of the types of treatments and regimens.

There’s “definitely a second cancer signal” with lenalidomide, but it could be related/augmented by other treatments given for the disease and further research could show how to minimize these effects, said McCarthy, director of the blood and marrow transplant program at the Roswell Park Cancer Institute, in an interview. Commenting on what some see as a small survival benefit in the CALGB study, McCarthy pointed out that crossover from the placebo arm to the treatment arm was allowed in the trial.

During the analyst briefing, Celgene’s Hugin commented that showing an overall survival benefit is challenging in myeloma, given that patients receive many different therapies after initial treatment, among other reasons, and regulators do not necessarily expect OS. However, they do want more assurance on the reliability of a PFS benefit. The CHMP wants to ensure that the rate of secondary malignancies will not have a negative effect on OS that would challenge the benefit of PFS.

In tan NEJM editorial assessing all three studies on May 10, University of Maryland hematologist Ashraf Badros said that the PFS benefits for Revlimid suggest value for maintenance after a “careful assessment of risks and benefits.” However, he also noted that other treatments, such as pomalidomide, appear to have efficacy in patients resistant to lenalidomide. As myeloma evolves into a chronic disease, doctors need to maximize available treatments and consider patients’ quality of life, he concluded at the end of his editorial.

Asked if the withdrawal in Europe could threaten guidelines in the U.S., Hugin said that the New England Journal of Medicine publications in May give even more “credibility and substance” about Revlimid to those managing compendia.

While revenue in Europe will be lower than expected without the new indication, Celgene says it will still hit its overall target for 2012 and longer term to 2015 even without approval for front-line/maintenance use in that region.

While revenue in Europe will be lower than expected without the new indication, the company says it will still hit its overall targets, even without approval for first-line use in that region, for 2012 and longer-term to 2015. The mix will be somewhat different by 2015 but the “model overall is going to hold,” said Jacqualyn Fouse, chief financial officer and senior vice president, during the analyst call. “If the current application for newly diagnosed never gets approved, we can still hit those targets,” she asserted.

The Great Maintenance Debate

Withdrawal of the indication in Europe comes at a time of continued debate about the value of maintenance treatment, considering the toxicities, costs and emergence of new treatment options at the time of relapse.

Per prices listed on the manufacturer website of $447.62 per 10 mg tablet, maintenance comes at the cost of $163,381 per year for the average patient, Badros noted in his NEJM editorial. “This total does not account for the costs of laboratory monitoring, physician visits and management of side effects,” he added.

In Europe, unapproved for the most part means unpaid, though doctors can attempt to convince reimbursement authorities to pick up the tab for off-label therapies. The U.S. has more of a tradition of insurance companies paying for oncology therapies on an off-label basis, particularly if they are included in compendia; listing in official compendia, like the National Comprehensive Cancer Network Guidelines, trigger coverage by Medicare. NCCN guidelines recommend Revlimid as a preferred option for first-line and maintenance treatment of multiple myeloma.

ISI Group analyst Mark Schoenebaum estimates that Revlimid has from 40% to 45% of the front-line market in the U.S., with very little first-line penetration in Europe.

Apart from concerns about cost, the clinical value of maintenance treatment is still being debated.

At the time the malignancies surfaced at the end of 2010, some U.S. payers commented to “The Pink Sheet” that secondary malignancies were unfortunately common with cancer treatments and that if the risk were borne out in the future, patients and physicians would need to weigh risks against benefits.

McCarthy said that currently in the U.S., despite the cost, some insurance companies do cover prolonged treatment with Revlimid, but others don’t.

During a session on controversies in myeloma treatment on June 2 at the American Society of Clinical Oncology annual meeting, the IFM study lead investigator Michel Attal noted the potential value of maintenance treatments, as long as they improve overall outcomes with acceptable toxicities. Based on studies to date, he asserted, none of the evaluated drugs have achieved this, including Revlimid and its predecessor Thalomid (thalidomide), as well as Millennium/Takeda’s competing Velcade (bortezomib).

These three drugs had revolutionized treatment of multiple myeloma, improving survival dramatically in a relatively short period of time Also see "Market Snapshot: Multiple Myeloma Drugs Promise To Live Up To Hype" - Pink Sheet, 15 February, 2010.. But a disease once characterized by a very bleak prognosis will soon have even more treatment options.

“In 2012, maintenance cannot be considered as a standard practice,” said Michel Attal, lead IFM investigator, at the ASCO annual meeting.

Also on June 21, Celgene announced that its Revlimid follow-on pomalidomide has been accepted for standard review by FDA in relapsed myeloma, with a user fee date of Feb. 10, 2013.

On June 20, FDA’s Oncologic Drugs Advisory Committee voted overwhelmingly to approve Onyx Pharmaceuticals Inc.’sproteasome inhibitor Kyprolis (carfilzomib), for relapsed/refractory multiple myeloma, a drug that could give Velcade a run for its money Also see "Onyx’s Kyprolis Sails Through FDA Panel, Boosted By Confirmatory Trial Plans" - Pink Sheet, 20 June, 2012..

In two out of the three lenalidomide studies published in NEJM, the drug failed to show a survival benefit and in the trial where it did show a benefit – the CALGB trial – the improvement was marginal, said Attal, professor of hematology at the Purpan Hospital in Toulouse, France.

Attal highlighted the increase in toxicities in the IFM 2005-2 study of long-term Revlimid – not only secondary malignancies, but also high rates of Grade 3-4 thrombocytopenia, neutropenia and infection.

In Attal’s view, we are still in the period of “scientific doubt” when it comes to Revlimid as a maintenance treatment. Some instigators will recommend it as a maintenance treatment, while others will recommend use only at the time of relapse, he said.

As for Velcade, maintenance studies showed an OS benefit but there are no studies testing the same induction treatment followed by maintenance with Velcade, compared to placebo maintenance. And Attal says the rates of neuropathy for intravenous Velcade as well as even the new subcutaneous version of that product are too high. I.V. and subcutaneous drugs are not practical for long-term maintenance treatment.

“I think that in 2012, maintenance cannot be considered as a standard practice. Indeed to be considered as standard practice, maintenance should delay relapse and improve overall survival with an acceptable toxicity. And today, none of the currently evaluated drugs have reached all these objectives,” he said.

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