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Morality rate of metastatic melanoma still high despite promise of PD-1 inhibitors

Long-term, 24-month follow-up data from the CheckMate 238 study showed that nivolumab adjuvant therapy improved RFS vs ipilimumab adjuvant therapy among patients with stage IIIB, IIIC and IV melanoma. However, we do not know yet whether there is a difference in OS. These follow-up data provided additional evidence that nivolumab is associated with substantially lower rates of adverse events compared with ipilimumab. So from that perspective, adjuvant therapy with nivolumab is an option for patients with stage III or IV receptive melanoma, and we would not use adjuvant therapy with ipilimumab as a first-line therapy for these patients.  

In addition, 4-year follow-up data from the KEYNOTE-006 study showed that pembrolizumab is beneficial among patients with metastatic melanoma vs ipilimumab. These patients who have a complete response with pembrolizumab tend to have a quite durable response. Two years after stopping therapy, the great majority of patients experience long-term benefits. What we do not know yet is the optimal duration for pembrolizumab in this population.

Although these data on long-term survivors are encouraging, the number of patients who are dying from their metastatic disease continues to increase. To that effect, we have to remember that although we have made great strides in patients with metastatic melanoma with PD-1 inhibitors, about 60% of patients will still die from their metastatic melanoma. So, we still have a long way to go.

Robert H.I. Andtbacka, MD, CM, FACS FRCSC
HemOnc Today Editorial Board Member
Co-director, Melanoma Clinical Research Program
Huntsman Cancer Institute
Associate professor of surgical oncology, University of Utah

Reference:
Leiter UM, et al. Abstract 9501. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Andtbacka reports advisory roles with Amgen, Merck and Provectus; investigator roles with Amgen, Provectus, Takara and Viralytics; and travel support from Amgen and Viralytics.

Second-generation CAR T-cell therapy effective against multiple myeloma

Results of a phase 1 study showed that chimeric antigen receptor T-cell therapy bb2121 had sustained efficacy among patients with relapsed or refractory multiple myeloma.

This is probably one of the larger series of CAR T-cells in myeloma with what I think is probably the best target in myeloma, B-cell maturation antigen (BCMA). So far, the responses from bb2121 seem to be durable and there is sustained MRD negativity, which is really exciting.  

A phase 2 trial is currently ongoing with the goal of enrolling a much larger number of patients, which we need to better understand the implications for this as a treatment approach. But I have no doubt that this kind of an approach will be successful.

Many of the patients in the phase 1 trial — and now phase 2 trial — have truly exhausted all available therapies. To see them respond, develop complete remissions, and have durable complete remissions is very exciting — not just from a provider perspective but also from the other side. Patients who did not think they had much time left have suddenly been given a new lease.

Obviously, phase 3 trials need to be done. One concern that often comes up is cytokine release syndrome (CRS) and its impact on the utility of the treatment. To me, CRS is an expected adverse event. In this trial, it is no different than what we would have expected for a CAR-T cell product. I think of CRS like tumor lysis syndrome — it is a sign that something is probably happening, and it is our job to figure out how to manage it, but it is not a reason to avoid the treatment.

Sagar Lonial, MD, FACP
HemOnc Today Editorial Board member
Chief medical officer of Winship Cancer Institute
Professor and executive vice chair of hematology and oncology, Emory University

Reference:
Raje NS, et al. Abstract 8007. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Lonial reports financial relationships with Amgen, Celgene, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Kite Pharma, Merck, Novartis and Takeda.

Community providers take on challenge of applying immunotherapy to practice

It is a common misconception that community oncologists lack knowledge in immunotherapy. That is not true at all. In fact, they probably administer immunotherapy much more frequently than most academic oncologists. However, their experience with immunotherapy comes a little bit later because academics are usually more involved with clinical trials. As a result, academic providers have been instructed how to manage adverse events of immuno-oncology as part of the trial protocol. For community providers, a lot of it is trial and error, as well as what they learn from colleagues, conferences and websites.

The paradigm of cancer is changing, and not just for community oncologists. The community care system has different challenges and structures than the academic system. Not all members of the community multidisciplinary team have the same information and experience. For example, about half of patients with melanoma receiving a combination of ipilimumab, which is a CTLA-4 inhibitor, and the PD-1 inhibitor nivolumab will end up in an ED. Their first contact will be with a triage nurse and the second contact will be an ED physician. Neither of these people will have much experience with immuno-oncology.

I am working with the Association of Community Cancer Centers (ACCC) to develop workshops and models by which we can communicate with the multidisciplinary team — including physicians, nurses and other medical care members — at their centers about treatment decision-making for patients on immunotherapy. We often find that doctors are seeing adverse events related to immunotherapy, but they do not know what they are. A patient with lung cancer on immunotherapy who presents with shortness of breath could have a range of conditions, including autoimmune pneumonitis, disease progression, underlying pneumonia, congestive heart failure, etc. Some clinical trials do not enroll patients with significant comorbidities, but those are the patients we treat. We are also realizing that patients with underlying autoimmune diseases are a lot more common than we thought. Some of the diseases that patients have predispose them to cancer. Should those patients receive immunotherapy? Or is their cancer escaping the immune system because the autoimmune disease somehow paradoxically activated the cancer in the first place? We do not know the answers to these questions. The way to approach this is not necessarily data gathering, but pragmatic planning to figure out how to implement the best practices in the community.

I think it is safe to say that 150,000 lung cancer patients per year in the United States alone are going to be receiving immuno-oncology agents in the first-line setting. Immunotherapy is now the bedrock of cancer care. Chemotherapy is almost adjunctive to immunotherapy in the most common metastatic cancer. When these agents became available, they were quickly adopted into the community at very high rates because it was so exciting, timely and impressive in terms of its efficacy.

The data are going to start getting very confusing very quickly. The age of reporting results from novel single-agent immunotherapy is over. Everything we are going to be seeing is combination therapy — either combination immuno-oncology agents or combined modality therapies such as chemotherapy plus immunotherapy or targeted therapy plus immunotherapy. We may even see completely different types of combinations such as radiation plus immunotherapy. They are all going to be tested and results will be coming out at exactly the same time for multiple different diseases with the same lines of therapy. Digesting that is going to be difficult, especially in the community and for those of us who subspecialize. The field of immuno-oncology is moving fast. Therefore, it will be very important for physicians to have decision trees and algorithmic pathways that are updated in real time.

Ari VanderWalde, MD, MPH, MBioeth, FACP
Working Group Member, Association of Community Cancer Centers Immuno-Oncology Institute
Director of research, West Cancer Center
Associate vice-chancellor of clinical research
University of Tennessee Health Science Center

Disclosures: VanderWalde reports being a consultant for Bristol-Myers Squibb and receives research funding from Amgen.

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