June 2014 Edition Vol.8, Issue 6

Immunotherapies at ASCO 2014: Checkpoint Inhibitors

Immunotherapies at ASCO 2014: Checkpoint Inhibitors

By Neil Canavan

“I’ve personally managed numerous patients on checkpoint inhibitors as part of clinical trials, and yeah, it’s very exciting…”
– John Nemunaitis, MD, Director of the U.S. Oncology Phase I Research Program

Immunotherapies are not a flash in the pan; they’re on fire and here to stay. This is the first of two articles highlighting the burgeoning field of cancer immunotherapies, featuring expert commentary from stakeholders in the immunotherapy space; interviews were conducted by OBR just prior to, during, and immediately following ASCO 2014.

“It’s clear that this immunotherapy revolution in melanoma – checkpoint inhibitors, in particular – are now spilling out into solid tumors,” said Steven O'Day, MD, of the Dana-Farber Cancer Institute, at an interview during this year’s American Society of Clinical Oncology (ASCO). No longer is the tumor the exclusive target. “The data are getting very exciting – it’s telling us that there can be less focus on the particulars of the cancer cell and more on how to make the patient’s immune system stronger and more directed against tumors. This really may be the best way to go.”

The checkpoint inhibitors are, in brief, a class of drugs intended to release the molecular brakes that cancer cells have applied to the body’s immune response. This approach is propelled by the fairly recent insight by immunologists that an intact immune system does indeed perceive the cancerous threat, but is prevented from racing to the rescue by an oncologic stop light.

Checkpoint Inhibitors Can Turn Red Lights Green

The first such drug to market, with great fanfare, including an article in the New England Journal of Medicine is ipilimumab [Yervoy; Bristol-Myers Squibb] an agent that blocks the “stop” signal issued by CTLA-4, a down-regulator of the immune response in patients with metastatic melanoma. Since the advent of Yervoy, the interest in, and pipelines dedicated to checkpoint inhibitors by manufacturers have exploded.

“Now we have several anti-PD-1’s [another stop signal],” said Dr. O’Day. “And this is even more exciting, as up to two-thirds of patients are having a significant benefit from these drugs, with long-lasting responses.” 

Indeed, durable response is a key selling point in immunotherapy. “This speaks to the fact that the immune system has flexibility and memory,” explained Dr. O’Day. “First you activate these T-cells [with a checkpoint inhibitor] against specific tumor targets, and then once they clear the tumor they can then go back into memory.” For any residual disease that may resurface, these T-cells are primed for a renewed attack. “That’s pretty extraordinary,” he commented.

The shift in the general discussion in the oncology community from will-they-work, to, how-are-we-going-to-use-them is now underway, and was illustrated by the three checkpoint inhibitor studies that ASCO chose to highlight during the meeting at a press briefing on immunotherapies. The trio of investigations was:

Ipilimumab vs. placebo in stage III melanoma, adjuvant setting (N=951), with results showing:

  • 25% reduction in cancer recurrence at three years (p=0.001)
  • 12% improvement in survival; however, the data are not yet mature for median overall survival
  • Grades 3 and 4 adverse events (42%) included diarrhea and colitis, but were considered transient and “manageable”

Anti-PD-1, pembrolizumab in metastatic melanoma (N=411)

This was the largest Phase 1 trial in this disease setting, with results showing:

  • Overall response rates of 44%, and 28% for treatment naïve, and prior ipilimumab-treated patients, respectively
  • 88% of responses were sustained at 2.7 years follow-up

    • At one year, the overall survival in this cohort was 69%

The primary investigator, Antoni Ribas, MD, PhD, David Geffen School of Medicine, stated, “These are remarkable response rates for an antibody that hits the immune system, and not the tumor.” Regarding overall survival, he said, “Until quite recently late-stage melanoma had a survival rate of 6 to 9 months. In this study, we have yet to reach median overall survival.”

Furthermore, with Grade 3/4 adverse events of only 12% (mainly itching and rash), “… this is one of the most benign therapies ever used in my clinic,” concluded Ribas. 

Nivolumumab (anti-PD-1) plus ipilimumab in metastatic melanoma (N=94), with results showing:

  • Survival at one year was 85%; at two years, 78%
  • Activity was seen regardless of BRAF mutational status
  • Grades 3/4 adverse events were seen in 62%

“Obviously, this [adverse events] raises concerns,” said Dr. Mario Sznol, Yale University School of Medicine, “but these events were expected with combination treatment and were manageable.”

Dr. O’Day took a step beyond the study’s conclusions and suggested that response rates for the combination were very similar to those seen with anti-PD-1 monotherapy. To distinguish between the two checkpoint approaches, and if ipilimumab contributes to the cause, he stated that “it’s the overall survival data that will tell the tale.”  

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