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:

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

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

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:

“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.”  

Immunotherapies at ASCO 2014: Checkpoint Inhibitors (continued)

A Tale Nearly Untold

Though the adjectives abound (ie, “most benign, unprecedented, remarkable”) checkpoint inhibitors were nearly passed on. “Pfizer had one of these in development,” recalled Gary Schwartz, MD, Chief of Memorial Sloan-Kettering’s Melanoma and Sarcoma Service, and Associate Editor of the Journal of Clinical Oncology. “But they abandoned it because patients were progressing in the first eight weeks of treatment. And what happened then was Jedd had a patient in the BMS trial [for Yervoy] who progressed at eight weeks…”

Jedd, being Dr. Jedd Wolchok, also of Memorial Sloan-Kettering, told the patient ‘come back in two months and we’ll see how you’re doing,’ not actually expecting to see the patient return because the guy’s liver was 80 percent replaced by tumor.”

Yet, eight weeks later the patient did return and he was seemingly healthy. “They did a CAT scan,” said Dr. Schwartz. “All those liver lesions? They were just the infiltration of T-cells fighting the cancer cells. Every one of those lesions was gone and the guy was in complete remission, and that’s been durable. That one single clinical observation probably saved the whole field of immunological therapies for Bristol-Myers Squibb.”

And for everyone else in the space – the Yervoy experience established that immunotherapies require different clinical trial endpoints, to whit: There may be early progression with these drugs, but a robust response then follows – indicative of the kinetics of a working immune system.

The wonder and timeframe of this activity aside, it’s also been established that checkpoint inhibitors, on their own, are not magic bullets.

“Tumors are more sophisticated than that,” observed Nabil Ahmed, MD, of the Center for Cell and Gene Therapy, Baylor College of Medicine. “Tumors look like a genetic mess, but this is a very organized mess. It’s almost like looking at a slum and thinking that this is a slum, yet, slums have systems. They are deranged; the same way as signaling is in tumors, and molecules are in tumors. Deranged, but they continue to function. There has to be a multi-mechanism to be able to collapse the tumor system.”

Critical to the mechanism is the presence of T-cells that can be activated, and this dynamic varies greatly between patients, and between tumor types. “If I look in my crystal ball, I see a future combination of a checkpoint inhibitor antibody with an infusion of T-cells (so-called TILs, or CARs).  I think this is what will make it work. We are not there yet, of course, because we’re still kind of testing each approach alone.”

Dr. Tim Bullock of the Human Immune Therapy Center, University of Virginia, concurs. “The weakness of checkpoint blockade at the moment is patients who don’t have preexisting responses in their tumors are very unlikely to respond to them.” No T-cells, no T-cell response. “Are we going to need vaccination strategies to amplify the immune response against tumor antigens, and then use the checkpoint inhibitors once these T-cells get into the tumor microenvironment?”

Indeed, such questions abound in the cancer immunotherapy space: Are there other ways to train the immune system to “see” the cancer cells? Is it simply doing damage to the tumor with chemo- or are radiotherapies going to elicit this immune response against those tumors? What about priming the tumor, as has been suggested, with agents known to increase PD-1 expression, which would, in a way, drive a tumor towards therapeutic vulnerability?  

“In the short term, I think combinatorial checkpoint blockade or the combination of checkpoint blockade with T-cell activation strategies are going to be very effective, but potentially very dangerous. So we have to be very careful moving forward.”

Bench to Bedside

The shiniest new therapeutic tool, even one as sophisticated as immunotherapy is useless if you’re afraid to use it. “I would say the majority of the community oncologists do have their finger on the pulse of what’s going on,” suggested Julie Brahmer, MD, Johns Hopkins University, “But they may or may not feel comfortable using some of these new therapies. Some of the community docs I’ve talked with who are using ipilimumab in their clinic say it’s not that easy, and that they don’t feel comfortable using it.” Even so, Dr. Brahmer sees the PD-1 antagonists as less toxic than the CTLA-4 targeting drugs. “They may be a little bit easier to handle in the clinic, and hopefully continuing education will increase physician comfort level.”

Dr. Michael Gordon, of the Arizona Center for Cancer Care, also sees the agents targeting PD-1, and PD-L1 (the PD-1 ligand) as more user friendly than the first-in-class approved drug, Yervoy. “The good news is that the PD-1, PD-L1 agents have a different safety profile than the other immune checkpoint inhibitors like ipilimumab, so the concern about the high rate of toxicity for colitis, skin rash, and endocrine system dysfunction, we’re not seeing that as quickly with these drugs. So I expect that we’ll see a much greater uptake.”

And to facilitate that uptake doctors may need to have a talk with their nurses. “We’ve known for a long time that patients are much more open with nurses than they are with physicians,” Dr. Gordon readily admitted. “I think patients fear that sharing their infirmities with their doctors will lead to dose modification, or dose reductions and a potential compromise of their therapy, and so the nurses become a crucial component of our patient care profile, and they [nurses] need to be educated on these immunotherapies so that they can bring to the physician’s attention, or on their own, execute processes for managing adverse events.”

At the end of the day, inclusion is what immunotherapy is all about. As Jedd Wolchok put it, “With these drugs we treat the patient, but it’s the patient that treats the tumor.”

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