October 2015 Edition Vol.10, Issue 10

Five Hits and a Dud: A Snapshot of the 2015 European Cancer Congress

Five Hits and a Dud:
A Snapshot of the 2015 European Cancer Congress

By Neil Canavan

The European Cancer Congress (ECC) 2015 meeting organizers made sure to remind their attendees that there’s more than cancer immunotherapy (IO) to hear about – innovations with targeted treatments continue to be made, and IO/targeted combinations are in the works. “This has to be a story of working together,” said Caroline Robert, MD, PhD, Institute Gustave Roussy, Paris, at the opening plenary session.

“In the future we are going to do immunogenic targeted therapy, and personalized immunotherapy, and there is no reason to have separate auditoriums to discuss these issues,” said Dr. Robert.

In the meantime, yes, checkpoints and chimeric antigen receptors (CARs) are the stuff of headlines, and rightly so, but many patients don’t respond to these new agents, and the remaining unmet clinical needs will have to be addressed with targeted agents used by themselves, or in immunotherapy combinations.

In that light, this review will touch on two immunotherapy (IO) presentations, and targeted agents showing significant activity in two settings of unmet clinical need.

Metastatic Kidney Cancer

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, with 338,000 new cases, and more than 100,000 deaths worldwide each year. “The five-year survival rate for those diagnosed with advanced kidney cancer is 12.1%, and so more effective treatments are desperately needed for these patients,” said Padmanee Sharma, MD, PhD, professor of immunology, MD Anderson Cancer Center, Houston, presenting her data on the CheckMate 025 trial.

The phase III, CheckMate 025 study compared nivolumab (Nivo), an immunotherapy drug that blocks the interaction between the programmed cell death receptor (PD-1) and its activating ligand (thereby “unmasking” the tumor so that the immune system can then recognize it) and everolimus, the standard of care (SOC) in this disease setting (N=821).

Having recruited its first patients in October 2012, CheckMate was halted in July 2015 due to the abundant evidence of efficacy. “After the interim analysis in July, the DMC [Date Monitoring Committee] concluded that the trial had already met its primary endpoint,” said Dr. Sharma. “It was clear by then that there was superior overall survival among patients being treated with Nivo.”

Randomized in a 1:1 fashion, patients who had previously failed SOC with anti-angiogenic agents were treated with either Nivo, or everolimus, until experiencing disease progression or unmanageable toxicity. Treatment beyond progression was permitted if either drug was tolerated and clinical benefit was noted.

Results showed that the overall response rate to treatment with Nivo was 25%, versus just 5.4% for everolimus. This activity translated into a superior rate of overall survival for the immunotherapy: a median of 25.5 months for Nivo was reported vs 19.6 for everolimus (HR 0.73; p=0.0018) (Figure 1). 

“Importantly, survival curves for the two treatment arms separated early and that separation was sustained throughout the remainder of the study,” Dr. Sharma said. Further, the survival advantage was still observed in patients in the poorest risk groups (as gauged by performance status).  

While this was all to the good regarding Nivo’s therapeutic efficacy, there was one puzzling finding from CheckMate 025: Nivo activity is not strictly linked to expression of its putative ligand target – the PD-L1 protein. For patients with ≥1% PD-L1 expression the median overall survival was 21.8 months, while for patients with <1% of PD-L1 expression the rate was higher: 27.4%.

“The finding that overall survival was higher among patients treated with Nivo, irrespective of PD-L1 expression, suggests that PD-L1 expression should not be used to determine which patients might respond to the therapy and whether or not to offer it to them,” concluded Dr. Sharma.

Regarding safety, the Nivo cohort experienced fewer serious adverse events, and those seen were consistent with previous use of the drug. The most common events related to Nivo were fatigue (33%), nausea (14%) and pruritus (14%).

Of note, regarding duration of response, even those patients who discontinued Nivo due to intolerability continued to respond favorably.

Due to the remarkable response rate observed in this trial, and the unquestioned unmet medical need, the results for Checkmate 025 were just published in the New England Journal of Medicine.

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