Bristol Offers Yervoy For Free In New Early Melanoma Indication

New program gives free treatment with the checkpoint inhibitor for up to three years to patients taking 10 mg/kg dose as adjuvant therapy after surgery.

Bristol-Myers Squibb Co. is offering free treatment for up to three years of the checkpoint inhibitor Yervoy in the newly FDA-approved adjuvant melanoma setting to patients who enroll in a special new program specific to the indication.

Yervoy (ipilimumab) was approved by FDA on Oct. 28 at the dose of 10 mg/kg for a new indication in adjuvant treatment of patients with fully resected Stage III melanoma. The CTLA-4 inhibitor would be given after surgery to prevent relapse. Per labeling, patients would get one infusion every three weeks, followed by an infusion every 12 weeks for up to three years.

This represents the first approval of a checkpoint inhibitor for the adjuvant setting. Interferon has been available as an option for this indication but has limitations in terms of efficacy and toxicity.

It’s a relatively small target population. Bristol estimates 3,100 cases are diagnosed every year in the US.

Yervoy was initially approved as a monotherapy in March 2011 at a 3 mg/kg dose across lines of therapy for metastatic melanoma and won approval at the same dose on Oct. 1 for use in combination with Bristol’s PD-1 inhibitor Opdivo (nivolumab) in first-line melanoma (Also see "Bristol Hits Sweet Spot On Checkpoint Inhibitor Combination Pricing" - Pink Sheet, 1 Oct, 2015.). It’s been a busy period in the space, as the approval of Amgen’s Imlygic (T-Vec) on Oct. 27 for melanoma followed on the heels of the combination’s clearance (Also see "Amgen’s Imlygic Approval A Milestone For Oncolytic Cancer Vaccines" - Pink Sheet, 27 Oct, 2015.).

Announcing Yervoy’s expanded label Oct. 28, Bristol said that to help ensure patient access in the adjuvant setting, it is offering a new patient assistance program – the Adjuvant Patient Program for Melanoma.

Patients prescribed Yervoy 10 mg/kg “for the adjuvant treatment of fully resected Stage III melanoma (lymph node >1 mm), whether insured or uninsured,” may receive the drug at that dose “free of charge for the duration of treatment, which may be up to three years,” the company said.

Offering free treatment is “pretty astounding,” Melanoma Research Foundation Executive Director Tim Turnham commented in an interview. As a monotherapy, the drug at a 3 mg/kg dose is given for a fixed course of four infusions, at the cost of $33,000 per treatment. At that pricing level, the 10 mg/kg dose would have cost about $100,000 per infusion and “the company knows that that’s just not acceptable,” he surmised.

Turnham also suggested that Bristol’s freedom to price the higher dose at a discount was limited.

It’s possible that reimbursement policy factored into the company’s decision-making on pricing.

If the company discounted the higher-dose regimen, this could set a new “best price” per mg/kg that would also apply to the lower dose for purposes of Medicaid rebates paid by the manufacturer.

For example, if a sponsor wanted to set a lower price for one indication versus another, the lowest price would prevail across the board in the eyes of Medicaid. Medicaid’s best price is viewed as a strong pricing floor that affects all markets in the US and limits the scope of discounting in the US (Also see "Creative Drug Pricing Hindered By Medicaid Best Price, Stakeholders Say" - Pink Sheet, 6 Oct, 2015.).

Asked whether Medicaid best price was a factor in its decision to give Yervoy for free, a Bristol spokesperson said that the company was thoughtful about program design while considering the “complexity of the current US reimbursement system.”

“Based on our analysis, we believe the current program structure is the best option for these patients,” the company said.

A Short-Term Issue

The difference in dosing for different lines of therapy is likely to be an issue just in the short term. Yervoy’s adjuvant approval was supported by the Phase III CA184-029 (EORTC 18071) study, which started in 2008 when discussion was ongoing about appropriate dosing to achieve the best risk/benefit profile. At the time, 10 mg/kg was selected for the adjuvant study, setting the path for the filing. Yervoy reduced the risk of recurrence by 25% compared to placebo in the study of 951 Stage III melanoma patients.

However, this dose was also associated with a lot of severe side effects that raised eyebrows upon presentation at the ASCO meeting (Also see "Yervoy/Nivolumab May Need Stronger Survival Data To Be First Choice In Melanoma" - Pink Sheet, 2 Jun, 2014.). Labeling notes that the rate of Grade 3-5 severe immune-mediated side effects was 41%. Five patients died in the study. The discontinuation rate due to adverse events was also high for Yervoy, at 52%.

Given the toxicities, uptake of Yervoy may depend on how physicians counsel patients. They could advise that patients hold off on Yervoy until disease becomes metastatic, however, there’s an emotional factor to consider for patients who are concerned that their tumors could come back at any time, Turnham said. Bristol noted that about 60% of Stage III fully resected patients do relapse.

Turnham expects patients at higher risk for recurrence will consider the option of adjuvant Yervoy “pretty seriously.”

Currently, it’s unclear whether the 3 mg/kg dose would be as effective with less toxicities in this line of therapy. Consequently, it’s also unclear whether insurance companies would cover the 3 mg/kg dose off label in this population and patients may wind up with a financial incentive to use 10 mg/kg instead, because it will be available for free, Turnham said.

Bristol noted in its statement that it is working with the Eastern Cooperative Oncology Group on an ongoing study of other dosing options for Yervoy in the adjuvant setting.

“Today’s approval is an important step in our commitment to bring our Immuno-Oncology pipeline to earlier lines of cancer treatment and to make new options available quickly while we continue to build upon our scientific understanding and develop even better solutions,” the company said.

Bristol’s CheckMate 238 trial tests Yervoy against Opdivo in adjuvant melanoma; the primary completion date for that trial is November 2018. Furthermore, the National Cancer Institute is running a study testing Yervoy against interferon in the adjuvant setting; the primary completion date is May 2018.