Cancer Immunotherapy at ASCO:
Bringing Down the House

By Neil Canavan

Cancer immunotherapy took over the spotlight at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO). For proof, look no further than the abstracts chosen for the opening session—all three focused on the immunotherapy (IO) drug class known as, Checkpoint Inhibitors.  

Dr. Neil Segal, Memorial Sloan Kettering Cancer Center, opened the session by giving a brief micro- to macro-view of the immunotherapy field.  

“In 2010, the first Phase 3 clinical trial with an immune checkpoint inhibitor, anti CTLA-4, ipilimumab, was reported. This study showed a survival benefit in advanced melanoma with a survival of 10.1 months for ipilimumab (plus the Gp100 melanoma vaccine) vs 6.4 months for gp100 alone.” This result was a revelation, and caught the attention of oncology researchers all over the world.

From that single trial sprung many. Of the 6,018 investigational studies now listed on Clinicaltrials.gov, 279 of them have an IO component. As Dr. Segal pointed out, “That’s one of every 22.”

Day One, for Openers: PD-1

Kicking off the meeting, and presented before a packed room were the interim results of a Phase 1/2 study looking at the use of the PD-1 (checkpoint) inhibitor, nivolumab, in a cohort of patients with advanced hepatocellular carcinoma.

“This disease is the second most frequent cause of cancer death,” said study investigator, Anthony El-Khoueiry, MD, University of Southern California Norris Comprehensive Cancer Center, Los Angeles. Sorafenib, a kinase inhibitor, is the standard of care in this setting, with median survival rates of 7 to 8 months. “There is no standard of care after failure on sorafenib.”

Dr. El-Khoueiry explained the rationale for using IO in this setting. “Typically, this is an inflammation-associated cancer and is immunogenic,” and therefore, has lots of T cells already in the vicinity of the tumor — T cells that are primed to have their activity unleashed by a checkpoint inhibitor. In a healthy individual the checkpoints block excess T cell activity in order to prevent autoimmune disorders.

As far as using nivolumab, which blocks the PD-1 receptor, it was previously shown that hepatitis infection is associated with an up-regulation of PD-1 expression.

This dose-ranging study enrolled HCV, HBV, as well as uninfected patients (N=200).

Results showed that, overall, 19% of patients experienced objective responses. “Two had complete responses, and 48% had stable disease,” said Dr. El-Khoueiry. Further, durable responses were observed across all dose levels and etiologic cohorts.

For survival, “Given the fact that many patients are still on study therapy, the overall survival (OS) data are preliminary.” That said, at 9 months the survival rate was 70%, and at one year the rate of survival was 62%. “To put this in context, the 12 month survival rate after sorafenib failure is about 30%,“ said Dr. El-Khoueiry.

Commenting on the results, Lawrence Fong, MD, UCSF, was optimistic. “Hepatocellular carcinoma represents another difficult-to-treat cancer where PD-1 axis targeting appears to have clinical activity, and with modest toxicity,” he said. “I think this really highlights an exciting development for patients with this challenging disease.”

PD-1 in NSCLC

Putting yet another feather in the nivolumab cap, Luis Paz-Ares, MD, PhD, Hospital Universitario Doce de Octubre, Madrid, presented results for the CheckMate 057 trial, an investigation comparing the use of nivolumab versus docetaxel in a cohort of patients with advanced, non-squamous, non-small cell lung cancer (NS-NSCLC; N=582) (Figure 1).

“These patients, after progression on platinum-based doublets, have few options,” said Dr. Paz-Ares. “The median overall survival is from 8 to 10 months.”

The rationale for using a PD-1 inhibitor in this patient setting is the activity observed with nivolumab in NSCLC patients with the squamous histology.

Results showed an overall response rate of 19% for the checkpoint inhibitor arm vs 9.4% for standard-of-care docetaxel arm (Figure 2). The median overall survival was 12.2 months for nivolumab vs 9.4 months for docetaxel (P=0.001). “With a hazard ratio of 0.73, this translates into a reduction of death otherwise expected of roughly 27%,” said Dr. Paz-Ares.

Increasing survival with nivolumab was observed to correlate with levels of PD-L1 expression; there was no improvement in survival reported for any PD-1 negative patients.

The discussant for this study, Roy Herbst, MD, PhD, Yale School of Medicine, said, “About 20 years ago some of us sat in a meeting in Los Angeles and we heard about Phase 1 studies of carboplatin and paclitaxel, and the wonderful response rates in lung cancer—look how far we’ve come.”

Nivolumab was recently FDA-approved for squamous cell NSCLC in March.

To be clear: “Is this the new standard of care for the treatment of previously treated, non-squamous non-small cell lung cancer?” asked Dr. Herbst. “Yes. This is a positive randomized Phase 2 trial that met its primary endpoint for all comers. This sets a new standard for previously treated disease, and now we need to move this to front-line therapy for the appropriate patients.”

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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