Summary
On March 25, the U.S. FDA granted the approval of Bristol-Myers Squibb's ipilimumab (Yervoy) for the treatment of unresectable and metastatic malignant melanoma (MM). Ipilimumab, a monoclonal antibody (MAb) that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), represents a turning point in the treatment of MM. Ipilimumab is the:

  1. first therapy to be approved for MM in more than a decade,
  2. first therapy to achieve a significant overall survival (OS) benefit for advanced MM
  3. first-in-class anti-CTLA therapy to be granted FDA approval

Ipilimumab is poised to change medical practice in a population that is devoid of effective treatment alternatives and is set to reap high commercial reward.

Analysis
Ipilimumab's regulatory approval was based on a pivotal Phase III (020) trial involving 676 previously-treated unresectable stage III or metastatic (stage IV) MM patients. Data for ipilumumab were first presented at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting, and ipilimumab was subsequently granted fast-track priority review designation in August 2010. The three-armed trial randomized patients to receive ipilimumab alone, ipilimumab plus a peptide vaccine (gp100), or gp100 alone. Patients who received ipilimumab alone had a significantly improved median OS (MOS) of 10.1 months compared with 6.4 months for patients who received gp100 alone (P = 0.003). Patients in the ipilimumab plus gp100 treatment group achieved a MOS of 10 months. One-year OS rates were almost doubled for patients who received ipilimumab alone (46%) and ipilimumab plus gp100 (44%) compared with gp100 alone (25%). Despite an unusual choice of comparator for the study, the OS improvement achieved by ipilimumab (10.1 months) is a marked improvement over traditional reference agents.

Ipilimumab is associated with severe and potentially life-threatening immunological adverse events. In the 020 study there were seven ipilimumab-related deaths (approximately 1%), which casted uncertainty over the safety of this immunotherapy. Ipilimumab's label carries a black-box warning for immunological adverse reactions and a Risk Evaluation and Mitigation Strategy (REMS) has been developed with the FDA to mitigate severe toxicities.

The 020 study enrolled patients who had already received systemic therapy for advanced or metastatic disease. Approximately 70% of patients enrolled had distant visceral metastases (stage M1c). Notably, the labeling granted for ipilimumab does not specify use in only previously-treated patients, but is inclusive of treatment-naive unresectable and metastatic MM. Of significance, the FDA's ODAC approval meeting was pushed back from December 2010 to allow the submission of further data. In March 2011, Bristol-Myers Squibb announced that ipilimumab (in combination with chemotherapy) as a first-line treatment for unresectable and metastatic MM had met its primary end point of OS in a pivotal Phase III (024) trial. First-line data for ipilimumab is expected to be presented at the ASCO 2011 Annual Meeting. The expansion of the label to include first-line patients is further evidence for the strength of the efficacy data and the favorable risk-benefit ratio.

As the first therapy to demonstrate OS benefit in advanced MM and as a first-in-class immunotherapy that blocks CTLA-4 activity, ipilimumab will command a high price. We anticipate that ipilimumab's high price, coupled with its broad labeling approval in unresectable and metastatic MM, will secure Bristol-Myers Squibb considerable sales from this novel immunotherapy. We anticipate that uptake of ipilimumab will be rapid and widespread owing to there being a lack of effective current therapies for advanced MM. Ipilimumab will quickly become established as the standard of care in this untapped market. Ipilimumab is also in Phase III development for the adjuvant treatment of MM (primary completion data is October 2012), and approval in this setting would significant bolster sales.

However, the emerging therapy pipeline for advanced and metastatic MM is becoming increasingly crowded. We anticipate that ipilimumab will face stiff competition from the launch of potentially multiple therapies. Most notably, Roche's RG7204 (vemurafenib; PLX-4032), an oral BRAF inhibitor, that has demonstrated impressive survival benefit and response rates in unresectable and metastatic MM. Roche is expected to file for regulatory approval in the first- and second-line setting of MM in 2011. As ipilimumab has an adverse safety profile and lacks a biomarker to indicate which patients are most likely respond to treatment, RG7204 may offer a more tolerable and personalized therapeutic alternative to ipilimumab.

Nevertheless, ipilimumab is heralded as a breakthrough by thought leaders interviewed by Decision Resources, and it holds great promise of transforming the medical practice of this difficult-to-treat malignancy. Approval of ipilimumab also represents a milestone in the field of oncology as it is the second immunotherapy to be granted FDA approval within the last 12 months Dendreon's sipuleucel-T (Provenge) won FDA approval for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (MCRPC) in April 2010. We anticipate that ipilimumab's approval will stimulate interest in developing immunotherapy for MM and indeed other oncology indications.

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