Pharma Strategy Blog

The latest New England Journal of Medicine dropped in the mail yesterday afternoon, it has some interesting articles on how palliation plus chemotherapy offers improved survival over chemo alone and a small study on the positive impact of T'ai Chi on fibromyalgia.  My attention, however, was drawn to the ipilimumab data in advanced metastatic melanoma.

We saw the first major presentation of this phase III trial recently at ASCO, and my pre-ASCO notes can be found here. At the BMS investor meeting held during the conference, the executives were clearly very excited about the prospects for the agent.  It would seem that the FDA agrees with them, as it was announced yesterday that Priority review status has been granted in previously treated people with melanoma.  The PDUFA action date is estimated as December 25th, 2010, so I think we can safely assume that it will likely happen a bit before that 🙂

Going back to the NEJM paper, what can we expect?

The complex study design looked at the impact of ipilimumab, which targets CTLA-4 antibodies resulting in anti-tumour effects, with and without gp100, a vaccine based on melanoma vaccine, versus ipilimumab alone in a phase III trial of 674 patients. In short, here's how the median overall survival results stack up:

• Ipilimumab + gp100:   10.0 months
• gp100 alone:               6.4 months
• Ipilimumab alone:      10.1 months

There was no difference in survival between the two ipilimumab groups, suggesting that the gp100 vaccine isn't adding anything to the mix. I'm not really convinced, however, of the arguments for using gp100 as an unconventional control over dacarbazine (DTIC) in patients who had previously failed IL2 therapy.  From this data, we have no idea how ipilimumab stacks up versus dacarbazine in the second-line setting, but given there is no standard of care in the refractory setting for patients who have failed dacarbazine, it presented a tricky issue in trial design. Still, the overall survival advantage in favour of ipilimumab alone speaks for itself.

It will be interesting to see what BMS do with this commercially, if the FDA approve it and they most likely will.  Based on this data, it appears to make sense to market ipilimumab alone without the extra costs and potential toxicities associated with adding gp100.

Four months improvement in advanced refractory melanoma is a relatively big jump, and like many I'm excited to see that, despite the low responses rates seen in the ipilimumab groups (6-11%).  The editorial by Hwu also noted that:

"… the true importance of this drug lies in the long-term benefit that was seen in a subgroup of patients. Follow-up from the earliest cohort of patients that received the anti–CTLA-4 drug shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years."

The biggest downside of this trial though, was the side effect profile. Whereas we recently saw few fatal toxic side effects associated with the Provenge vaccine in castrate-resistant prostate cancer, immunotherapy with ipilimumab is an entirely different kettle of fish, as the NEJM article demonstrated:

Grade 3-4 immune related adverse events:

• 10-15% of ipilimumab treated patients
• 3% treated with gp100 alone

Deaths in study:

• 14 related to study drugs (2.1%)
• 7 associated with immune-related events

Now, we need to remember that people entering clinical trials at Academic centres are not the typical patients seen in the Community setting.  They tend to be younger and have a much better performance status for a start, so it is likely that there will be some nervousness associated with management and complications in older, more frail patients. The authors noted that:

"Adverse events can be severe and long-lasting, or both, but most are reversible with appropriate treatment."

It reminds me somewhat of the situation with another immune-related therapy a few years ago with alemtuzumab (Campath), an monoclonal antibody that binds to CD52 in chronic lymphocytic leukemia (CLL), where the occasionally urgent side effect management and rare complications that can arise (CMV activations, severe infections etc) were so resoundly disliked by the Community, that most avoid using it where at all possible. Urgent medical attention of severe and, potentially fatal, complications is much easier to handle in a hospital than an office setting, especially on a Friday afternoon or over the weekend.

Ipilimumab looks to be an efficacious therapy that extends life, but at a cost.  I can therefore see that it will mostly likely get used in Academic settings, where there is more comfort and familiarity in dealing with the potential complications, especially in advanced, relapsed disease.  I could be wrong in that assessment, but that is what instinct tells me.

Most doctors will try something once, especially in the refractory or salvage setting, but the first sign of potentially fatal complications requiring urgent medical attention creates an environment that is fraught with stress and worry, busy Community practices may well decide it will be easier to refer appropriate patients in that situation.

In an accompanying editorial (see below for reference link), Patrick Hwu summed up the trial and new directions in metastatic melanoma admirably:

"Despite dramatic effects in a subgroup of patients receiving the anti–CTLA-4 drug, the majority of patients with metastatic melanoma do not respond to this agent, and further work is vital to improve these results.

Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. Instead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevating the “tail” of the survival curve."

{Disclosure: Long on BMS}

Hodi, F., O'Day, S., McDermott, D., Weber, R., Sosman, J., Haanen, J., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J., Akerley, W., van den Eertwegh, A., Lutzky, J., Lorigan, P., Vaubel, J., Linette, G., Hogg, D., Ottensmeier, C., Lebbe, C., Peschel, C., Quirt, I., Clark, J., Wolchok, J., Weber, J., Tian, J., Yellin, M., Nichol, G., Hoos, A., & Urba, W. (2010). Improved Survival with Ipilimumab in Patients with Metastatic Melanoma New England Journal of Medicine DOI: 10.1056/NEJMoa1003466

Hwu, P. (2010). Treating Cancer by Targeting the Immune System New England Journal of Medicine, 363 (8), 779-781 DOI: 10.1056/NEJMe1006416