Immunotherapy in Cancer Care: Understanding the Impact of Shifting Treatment Paradigms in the Managed Care Setting
Panelists discussed the positive and negative aspects of using immunotherapy, traditional chemotherapy, and combination regimens. They addressed the importance of promoting both patient and provider understanding of immunotherapy. Finally, panelists discussed the cost associated with immunotherapy in cancer care.
The discussion was moderated by Peter Salgo, MD, a professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at NewYork-Presbyterian Hospital, New York City. The panelists included:
• Jeffrey Weber, MD, PhD, senior member of the H. Lee Moffitt Cancer Center and director, Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida.
• Michael A. Kolodziej, MD, national medical director, Oncology Solutions, Aetna, Inc.
• Daniel J. George, MD, Duke Cancer Institute...
Dr Salgo: The way I’ve looked at it, if I may, is in the past when you gave chemotherapy, you just killed all the cells and hoped that the rapidly dividing cells went first and then salvaged patients back. That’s not what’s going on.
Dr George: This is a really different paradigm. The immune system is present and we are trying to manipulate it in a way to reactivate it against cancer. There’s a concept called tolerance where, by multiple different strategies, cancer cells can evade recognition by the imanothermune system; there’s a way of reharnessing the immune system by overcoming that tolerance. Unlike chemotherapy or radiation therapy, where the treatment stops when you stop the drug, these are therapies that potentially could keep going and keep working following reactivation. We’re actually sort of vaccinating, if you permit me to use an umbrella term that may be imprecise, against cancer such that you are sensitizing an immune system against a particular tumor. You don’t have to re-vaccinate every 3 days. You give it once and the immune system keeps working...
Dr Salgo then asked Dr George to comment on the newly approved mover-and-shaker drugs in literature.
Dr George: I’ll simply walk through the clinical data and the mechanism of action of these drugs. Provenge is an autologous cellular immunotherapy from the patient’s own cells. It’s really the ultimate in personalized therapy. The drug is made from the person’s own cells through a process called leukapheresis; the cells are then shipped to a centralized laboratory and activated ex vivo against antigens that are relevant to prostate cancer, in this case, a fusion protein, a prostatic acid phosphatase in GMCSF (granulocyte macrophage colony-stimulating factor), an immunostimulant. That creates, within that peripheral blood mononuclear cell compartment, some activated cells against those proteins, which are then reinfused back in 3 days later, almost like a blood transfusion for the patient, an autologous blood transfusion. It’s repeated every 2 weeks for 3 doses. So it’s a 0-, 2-, and 4-week regimen.
Of 2 independent clinical trials, a relatively small randomized study demonstrated an overall survival advantage of about
4 months and a second pivotal trial, 512 patients randomized, demonstrated about
a 4.1 month improvement in overall median survival with a hazard ratio of about
0.77. And interestingly, as alluded to by Dr Weber, the patients that live longer derive a greater benefit. So a landmark analysis at 1 year demonstrates about a 12% improvement in survival, about a 24% improvement in overall survival by 2 years, while patients that are out to 3 years, there’s a 32% improvement in overall survival for that population, showing an absolute benefit that’s much greater. Bottom line, identifying the patients who are destined to live 3 years is ideal to treating with Provenge.
Dr Salgo: And, again, with just 3 doses, you know up front what it’s going to cost.
Dr George: But the benefit is extended over the lifetime of that patient.It’s not position: absolute;100,000 for 1 month. It’s an investment in a patient that we believe is going to live 3 years or more. If you annualize that out, it’s $30,000 a year. I don’t want to make it sound like it’s a black and white thing. This is against 1 antigen that may or may not be relevant, and some or many of these patients may not necessarily fully respond to that. I view this more like a platform. Because it has very low toxicity, there really isn’t a longterm residual toxicity from this treatment, in addition to the opportunity to building on this with subsequent therapies, whether targeted, immunologic, or otherwise. We’d now like to build and improve on this therapy...
Dr Salgo then asked the panelists to compare the safety profiles of Provenge and ipilimumab relative to traditional chemotherapies.
Dr George: With Provenge, because we’re activating ex vivo, an infusion reaction occurs following reinfusion, likely due to the induction of cytokines within that cellular mix. It results in a very acute, short-term, generally mild inflammatory profile: fever, chills, and back pain. Less than 3% incidence of grade 3, or what we consider serious adverse events, for any one of these toxicities is observed, which is short-lived, and completely resolves within 24 to 48 hours in the vast
majority of cases. So cumulative toxicity, residual toxicity, or end organ damage that are typical of chemotherapy or targeted therapy, in some circumstances, are not observed.
Dr Weber: The beauty of a vaccine against cancer is it will not be toxic. Ipilimumab and PD-1 antibodies are a different scenario because here you’re breaking tolerance. If you break the self tolerance of the immune system, it indirectly increases the ability to recognize the cancer, but there will be some collateral damage. about
10% or less of the patients who get ipilimumab will have grade 3 and 4 clinically meaningful serious adverse events that we call IRAEs, or immune-related adverse events, including colitis, inflammation of the pituitary or hypophycitis, low thyroid, rashes, rarely pancreatitis, or hepatitis, all manageable. And I probably spent 8 or 9 years figuring out how to manage these things, and I’ve written on it extensively. But there will be a cost in side effects.
Dr Salgo then asked the panelists to discuss the associated costs. How can such expensive treatments, sometimes in the range of $90,000 -100,000, be remunerated?
Dr Weber: Overall survival is the goal. That’s what we’re judging these drugs by. So, the cost estimate should not be in terms of the cost for that month, but rather in terms of the course of that life...
On future directions in cancer immunotherapy:
Dr George: I think this is the most exciting area in cancer research right now. As Dr Weber alluded to, there’s a lot of targets we haven’t hit yet. We’ve just started hitting some of these checkpoint inhibitors.…Although only in the early years of immunotherapy, what’s critical is the credibility that has been established by these therapies in terms of overall survival benefits and long-term disease-free survival benefits with the checkpoint inhibitors. Precision, recognizing for individual patients what those checkpoints might be or what those antigens might be, recognizing newer clinical settings, and how we build on all these findings, is going to be critical. Currently, we’re developing these drugs in the most metastatic refractory settings, but where we envision immunotherapy working best is probably in the more curative settings of adjuvant settings or minimal disease state settings. I hope there’s a change in the population of patients we can treat as well as the armamentarium we have to treat them with in a precise and directed way that will make it rational, effective, and hopefully real valuewww.ajmc.com/publications/evidence-based-oncology/2014/february-2014/immunotherapy-in-cancer-care-understanding-the-impact-of-shifting-treatment-paradigms-in-the-managed-care-setting/1
" The bottom line is: You have a prospective randomized trial and it held up to scrutiny and you got a survival benefit. On the other hand, you treat a population of men in this way and they live longer than the population of men not treated in this way."
Dr.O. Sartor about