June 2015 Edition Vol.11, Issue 6

Cancer Immunotherapy at ASCO: Bringing Down the House

Cancer Immunotherapy at ASCO:
Bringing Down the House (cont.)

Day 2: The Award

Further proof that IO has the eyes and ears of ASCO: on day two, the highest honor achievable at the Society, the David A. Karnofsky Memorial Award, was bestowed upon Suzanne Topalian, MD, Melanoma Program Director, and premier immunotherapy investigator at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

Presenting the award, past ASCO president, Clifford Hudis, MD, said, that Karnofsky award recipients hold a special place at ASCO because their accomplishments tell the story of our progress against cancer. “[Dr. Topalian’s] basic science studies of antitumor immune responses have provided a foundation for the translational development of immune therapies for melanoma, and other cancers, cancer vaccines, adoptive T-cell transfer and immuno-modulatory monoclonal antibodies.”

“Dr. Topalian’s landmark publication in 2012 showed that (nivolumab) produced dramatic responses not only in some patients with advanced melanoma, but also in those with lung cancer, the world’s most common cause of cancer death.”

In accepting the award, Dr. Topalian illustrated one of the main reasons that the concept of IO is so compelling—it’s simplicity. 

“While I was in medical school my father, who was not a scientist or a physician, asked me how things were going in medical school and specifically he wanted to know why it was taking so long to cure cancer.” This was 1975, four years after the war on cancer was launched.  

“I patiently explained that cancer was really at least a hundred different diseases and that this was a very complex situation,” said Dr. Topalian. “But his response was, ‘this is not complicated, it should be simple, all you need to do is find the common denominator’.”

PD-1 is one such common denominator. You don’t need to know what the tumor antigen is, you don’t need to characterize the target, you just need to let the immune system do what it’s designed to do, and checkpoint inhibitors do that.  

Even at this relatively early stage of clinical use, it’s clear that these drugs are game-changing. “Immunotherapy has now earned its place as one of the pillars of oncology alongside more traditional modes of treatment,” said Dr. Topalian.

Yet, this is just the beginning. A multitude of combinations are coming. “Cancer vaccines are now having a renaissance,” said Dr. Topalian, “specifically, as drugs that can be used in combination with checkpoint blocking drugs,” not to mention the countless combinations of checkpoint inhibitors with chemotherapy, and targeted therapy now being proposed.

The Plenary

Of the four talks chosen for the plenary session, IO was the first and clearly the most prominent.

Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center, presented the results of CheckMate 067, an investigation that combined two types of checkpoint inhibitors, anti CTLA-4, ipilimumab, and the anti-PD-1 inhibitor, nivolumab, and compared the combination to either agent alone in a population of patients with advanced melanoma.

The combination makes sense because it targets different immune system interactions; the PD-1 pathway inhibits crosstalk between tumor cells and T cells; CTLA-4 acts at the interface between antigen presenting cells and T cells (Figure 3).

Both have previously shown remarkable single-agent activity in advanced melanoma. 

This Phase 3 study randomized treatment-naive patients with advanced melanoma (N=945) between three treatment arms. Patients were treated until they experienced disease progression or serious toxicity.

Results showed that the progression-free survival for the ipilimumab + nivolumab arm was 11.5 months, 6.9 months for nivolumab alone, and 2.9 months for ipilimumab alone (Figure 4). Hazard ratios demonstrated a 26% reduction in disease progression for the combination arm vs the nivolumab alone arm.

There were an expected higher number of Grade 3/4 adverse events with the combination, but there were no on-treatment-related deaths.

Of note, “67.5% of those patients who discontinued due to toxicity had a response,” said Dr. Wolchok, “and half of those responses were after treatment had ended.”

Indeed, a later than expected response is a hallmark of cancer immunotherapy.

In discussing these results, Michael Atkins, MD, Lombardi Comprehensive Cancer Center, Washington DC, was both direct, and circumspect. “Given these results, ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma.”

However, “The combination of two expensive antibodies raises legitimate concerns about cost and value,” he said, “but we need to withhold judgment until we determine if the combination produces very long-term responses, or cures, which may reduce the need for other therapies. Furthermore, because of its early onset for toxicities in contrast to the long duration of monotherapy, the combination might actually involve less treatment and expense.”

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