Scroll Top

Cancer Paradigm Explodes: Patients May Win Big

After decades of searching for magic bullets against genetic errors that “drive” tumors, cancer researchers have been dealt a major curveball. It looks like the best way to treat cancer isn’t a strategic attack on the tumor, but just empowering the patient’s own immune system.

This field, immunotherapy, seemed dead not so long ago. But in the wake of eye-popping drug trial results, the massive cancer drug enterprise is taking a sharp turn and disrupting every business or organization affiliated with it.

Drug developers, diagnostics firms, research labs, CROs, insurers, medical facilities and more all need to adjust. Cancer drugs are going to be radically different going forward, and the testing and use of those drugs will be different too.

The norm will be bigger trials early on, more combinations of all types and a renewed interest in biomarkers to guide this much more complicated treatment process.


One clear sign of immunotherapy’s potential is that all the big pharma and biotech companies have barreled into it at an unprecedented pace. Then, just this week, immunotherapy start-up Juno announced it raised $120 million dollars based on “unprecedented” Phase I trial results. It’s one of the largest biotech financings of its type in the sectors history.

The tide has shifted so dramatically, some analysts are predicting that 50% of all cancer treatment could involve immunotherapy within the next decade.

How did this happen? The immunotherapy trend has been brewing for a while, but developed big momentum just this fall. At the 2013 European Cancer Congress in September, researchers presented pooled data showing that some advanced melanoma patients have lived as long as ten years on Bristol Myers Squibb’s immunotherapy Yervoy (ipilimumab).

The presentation included data from about 3,000 patients not enrolled in clinical trials, for 4836 patients in total: A very respectable data pool. Median survival was less than ten months overall, but just over 20% of patients were still alive after three years. The researchers noted a “plateau” in survival, which stretched from year three of treatment, to as long as ten years.

Those data are explosive.

Bristol Oncology VP Renzo Canetta discussed them at a recent cancer meeting in Boston. As he showed the striking survival graph, he noted “These included patients with metastases in vital organs.”

Many have wondered at immunotherapy’s revival, since it has failed so spectacularly in the past. One scientist at the Boston meeting suggested that perhaps we have just finally found the pathways that really matter.

It’s growing more likely that that’s exactly what’s happened. In July, a couple of New England Journal of Medicine papers described more remarkable results of combination immunotherapy in metastatic melanoma. In a Phase 1 trial of Bristol’s Yervoy and another immunotherapy, nivolumab, 65% of patients in one arm of the study showed some clinical activity. In just over half the patients, the tumor shrunk by 80% or more.

Another study, using Merck and Co. Inc’s immunotherapy MK-3475, delivered similarly impressive results. Even patients who had relapsed on Yervoy showed sustained responses to MK-3475: That’s crucial, given how resistance has proved such a problem with targeted therapies. MK-3475 has since become a centerpiece in Merck’s oncology strategy.

And there is more. Bristol recently released new data from a Phase 1 lung cancer study of nivolumab. The study included 129 heavily pre-treated NSCLC patients, and showed sustained activity, with one- and two-year survival rates of 42% and 24%, respectively. Again, unprecedented results.

“The potential for cures with these immunotherapies is enormous,” Canetta said at the Boston Meeting. “But now, we must shift the curve.” That means finding ways to increase the number of patients who respond to such drugs.

Here’s where the challenge and the opportunity comes.

Bristol is in the lead of this race now, combining Yervoy and nivolumab in a range of cancers. Early results from in renal cell carcinoma and non-small cell lung cancer are expected before the end of this year. Those will reveal a lot about where the field is headed, because the two drugs are complimentary: They target different immune molecules in the same pathway.

Yervoy was approved in 2011 and netted more than $700 million in 2012. Analysts have estimated that nivolumab could reach peak annual sales of $4 billion. It’s no wonder every other big pharma or biotech is investing heavily in immunotherapies. More potential start ups like Juno, are also probably lurking in the wings, these changes things drastically for anyone in the cancer drug development field.

Big Changes

For one thing, side effects from these drugs are quite different from traditional chemotherapy or targeted therapies. “You are eliciting an autoimmune response, you’re going to see effects,” Canetta pointed out. The vitiligo that some patients experience on Yervoy, for example, “is a sign the treatment is affecting immune activity.” Canetta added that Bristol, “has seen no upsurge in immune effects,” even after a decade of following patients. That’s comforting.

The company has also given doctors and their staff detailed information about expected side effects and how to deal with them. Side effects from immune therapies can look similar to what is seen with chemotherapy “but the mechanisms can be different and they can require different responses,” Canetta explained.

Other obstacles include finding a regulatory pathway for novel combinations such as targeted drugs plus immunotherapies, determining whether drugs should be administered sequentially or concurrently, and figuring out which combinations are the most effective and which may be too toxic. The combination of Roche/Genentech’s BRAF-inhibitor vemurafenib and Yervoy in one trial, for example, led to an unanticipated overlap in toxicity.

“With immunotherapy, we are seeing a new paradigm emerge with the potential for curative treatment,” said Jeffrey E. Settleman, Senior Director of Discovery Oncology at Genentech, South San Francisco, in an interview. “That is not something we are getting with targeted treatment in general.”

Research also now suggests that most tumors are highly heterogeneous and have subpopulations of cells with distinct vulnerabilities. A single targeted therapy is unlikely to have much effect on its own.

The excitement about immunotherapies is so high, even early stage trials of promising cancer drugs are now drawing larger numbers of patients and companies are embracing novel types of combination therapy trails.

Novartis, for example, is studying its RAF kinase inhibitor LGX818 in combination with five other drugs, including a MEK and cyclin-dependent kinase inhibitor, in a trial with an adaptive design. Even more revolutionary, the “Master Protocol” lung cancer trial will test five drugs from five different companies in a bold trial design aimed at separating winners from losers as early as possible.

All of this is encouraging, but how will we figure out the right combinations of treatments? How will we detect whose responding to what treatment sooner? Can drug companies still charge $100,000 or more/per year for cancer drugs if the patients are living more than a decade? Should insurers start sponsoring biomarker trials?

These and more pressing questions remain. But at least patients with cancer have something truly promising to look forward to: Cancer, even the metastatic type, as a potential chronic disease.

See Article