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ASCO Roundup: Checkpoint Combos, Tumor Profiling, Financial Toxicity

Xconomy National — 

[Note: Ben Fidler coauthored this report.] The American Society of Clinical Oncology conference is wrapping up, and the closely watched medical meeting-slash-hype machine produced its usual array of data. There were a few big business-focused “horse race” stories—one company’s stumble was another company’s gain—but much of the news consisted of mid-trial updates that companies produce because, well, it’s ASCO and everyone is watching.

Drug costs remain a big worry, but there was no galvanizing moment like two years ago, when Leonard Saltz of the Memorial Sloan Kettering Cancer Center fired a broadside at the drug industry over the prices it was demanding for its new drugs.

Saltz was on hand this year, too, and sat for an interview with Medscape that’s worth a read. But there seemed to be a relative lack of headlines about drug costs. There was not, however, a lack of papers trying to measure “financial toxicity” as a side effect that’s just as tangible for a patient as an overheated immune system or debilitating nausea. One study also looked at the barriers that impede doctors from discussing with their patients the financial burdens of medicine. As people digest the ASCO data in the coming weeks, expect to see more discussion of drug costs, such as this urologist’s take in Forbes.

What else was shaking in Chicago? Read on.

CHECKPOINT BATTLES AND A NEW ENTRANT

—Checkpoint inhibitors, which stymie proteins such as PD-1 and CTLA4 that tumors use to evade the immune system, are now established cancer treatments: six have been approved for skin, lung, bladder, and other cancers.

The two checkpoint leaders—nivolumab (Opdivo, from Bristol-Myers Squibb (NYSE: BMY)) and pembrolizumab (Keytruda, from Merck (NYSE: MRK))—are in a topsy-turvy battle for market supremacy. Last year, nivolumab failed a key trial in newly diagnosed lung cancer patients, and pembrolizumab didn’t. Bristol-Myers is looking to rebound by combining nivolumab with another of its immunotherapy drugs, ipiliumuab (Yervoy), in newly diagnosed lung cancer patients. The latest detailed results from an early-stage study, Checkmate-012, were released Saturday. (A much larger study of the same combination, called Checkmate-227, is ongoing and has not produced public data yet.)

Checkpoint inhibitors continue to expand into other cancers. ASCO featured updates from nivolumab and pembrolizumab studies in liver, stomach, cervical, and colorectal cancers. Merck also reported more data underscoring pembrolizumab’s recent approval for patients with a particular genetic signature, regardless where their tumors originated.

Longtime partners Regeneron Pharmaceuticals (NASDAQ: REGN) and Sanofi (NYSE: SNY) have entered the checkpoint scrum with their PD-1 blocker REGN-2810, starting in an indication with no PD-1 inhibitors, advanced cutaneous squamous cell carcinoma, a type of skin cancer that also has no widely used standard of care. Their Phase 1 results, posted Sunday, were “interesting” but too early to draw much from, Barclays analyst Geoff Meacham wrote in a research note. A Phase 2 study is ongoing.

TARGETING TUMOR DNA

Just before ASCO, the FDA approved pembrolizumab to treat tumors with a specific genetic fingerprint regardless of the part of the body where they began growing. Over the weekend, Loxo Oncology (NASDAQ: LOXO) added to the enthusiasm for genetically-targeted cancer therapy with Phase 2 data that showed people with a wide range of tumors, all with a mutation called a TRK fusion, responded well to the company’s drug larotrectinib. Shares of Loxo surged more than 43 percent.

Loxo will soon seek to have larotrectinib join pembrolizumab as an approved tumor-agnostic drug, but in the meantime the trial’s lead investigator told Xconomy that the positive results could push more researchers and companies to “engage in this newer paradigm of drug development.”

A big hurdle, however, is acceptance of the tests required to identify a tumor’s signature. The cutting-edge DNA tests are not easily reimbursed and remain confusing for many doctors who don’t have access to the resources of major medical centers, as Xconomy reported last week.

Some of these tests look for TRK fusions, but Loxo’s CEO told Xconomy he is hedging bets, enlisting Roche to develop an older-school (and cheaper) test that looks at a tumor under a microscope.

Meanwhile, companies that make tumor DNA diagnostics were in full force at ASCO. One developer of blood-based diagnostics known as liquid biopsies, Grail, began the ASCO run-up with a merger announcement, then presented early data from its massive clinical study program.

Grail wants to make tests that screen for cancer—that is, detect it in otherwise healthy people. Others have similar ambitions, also using liquid biopsies. But these tests, which look for bits of tumor floating in a blood sample, are also being developed to use on patients already diagnosed with cancer. One liquid biopsy maker, Guardant Health, said at ASCO that comparisons across thousands of patients show its blood tests identify the same mutations as tissue biopsies a large percentage of the time.

IMMUNOTHERAPY COMBOS: THE VAST MATRIX

In one of Xconomy’s two ASCO previews, we highlighted the glut of immunotherapy combinations in clinical testing, and the potential backlash from the likely failure of many of these trials. Two days later, EP Vantage checked in with a tally of combo studies involving anti-PD-1 or anti-PD-L1 therapies. The 765 listed on clincialtrials.gov is more than triple the 215 running when EP Vantage checked in November 2015. Merck leads with 268 combo trials with pembrolizumab, followed by Bristol-Myers and its 242 nivolumab combination trials.

In this vast matrix of combinations, perhaps the most closely watched involves a class of drugs called IDO-1 inhibitors, named after the metabolic enzyme they target.

The hype surrounding these drugs is substantial: Incyte (NASDAQ: INCY), which leads the pack, is valued at more than $27 billion, even though its epacadostat has only produced data in small, early-stage trials. Incyte provided Phase 1/2 data from a combination of epacadostat and pembrolizumab in lung cancer patients, and a Phase 1/2 study of epacadostat and nivolumab in head-and-neck cancer patients.

Newlink Genetics (NASDAQ: NLNK) produced data on two IDO-1 blockers. Navoximod is being combined with Roche/Genentech’s atezolizumab (Tecentriq); indoximod failed a study in breast cancer.

PARP WALK

Another type of combination worth watching involves what’s known as a PARP inhibitor, a relatively new class of drug already approved in ovarian cancer. A Phase 1/2 study called TOPACIO, for instance, combines FDA-approved niraparib (Zejula) from Tesaro (NASDAQ: TSRO) with pembrolizumab in ovarian or breast cancer patients. Tesaro provided initial data Saturday, with more mature results expected later this year. AstraZeneca has an early-stage study of its own on the way combining its PARP inhibitor olaparib (Lynparza) with its PD-L1 blocker, durvalumab (Imfinzi).

There was plenty of news about PARPs working alone, too. AstraZeneca made the case that olaparib could be the first one to break into breast cancer. The Phase 3 study OlympiAD compared olaparib to chemotherapy in HER2-negative patients with a specific genetic mutation. Olaparib reduced the risk of death in these patients by 42 percent; the results were published in the New England Journal of Medicine.

Pfizer acquired PARP blocker talazoparib when it bought Medivation in August 2016. It released Phase 2 results in breast cancer Saturday and reported that its Phase 3 trial for talazoparib is now fully enrolled.

CAR-T UPDATES

With Novartis (NYSE: NVS) and Kite Pharma (NASDAQ: KITE) both hoping for an FDA approval, the field of T cell therapies known as CAR-T could see commercial daylight this year in two blood cancers where patients have had no luck with other treatments. Novartis’s product is for kids with acute lymphoblastic leukemia (ALL); Kite’s is for adults with non-Hodgkin lymphoma (NHL).

After several deaths doomed its lead program for ALL last year, Juno Therapeutics (NASDAQ: JUNO) said its new top priority, a treatment for NHL, is making progress in a large Phase 1 trial.

Beyond leukemia and lymphoma, however, the case for CAR-T is murkier, as Xconomy reported in March. One indication that has attracted several entrants is multiple myeloma, a cancer of plasma cells in the bone marrow. Early clinical studies began to report data late last year.

Bluebird Bio (NASDAQ: BLUE) continued its positive drip of Phase 1 data, and new entrant Nanjing Legend Biotech stepped into the spotlight with late-breaking data on 35 people in a trial being conducted in China.

PFIZER’S MEDIVATION GAMBLE TAKES A HIT

In that Medivation deal, Pfizer also wanted the successful prostate cancer drug enzalutamide (Xtandi). As Leerink Partners analyst Seamus Fernandez wrote in a note Monday, data at ASCO show how Medivation has gone from a coveted asset to an “exemplar of the dangers of competitive auctions and over-priced acquisitions.” Two studies published in the NEJM on enzalutamide rival abiraterone (Zytiga), from Johnson & Johnson (NYSE: JNJ), showed that abiraterone plus hormone therapy cut the risk of death in men with newly diagnosed, metastatic prostate cancer by a third compared to hormone treatment alone. The results, the study authors told Bloomberg, suggest that the front-line standard of care for these patients should change. Should that happen, Fernandez wrote, enzalutamide will largely get “pushed to the ‘back of the bus’ in terms of treatment sequence.”

PUMA RISES ON ROCHE BREAST CANCER DATA

Roche owns trastuzumab (Herceptin), the standard of care for HER2-positive breast cancer, but with looming generic competition it wants to extend the franchise. Its attempt to combine trastuzumab with its own pertuzumab (Perjeta), however, showed just the slightest benefit over trastuzumab alone. The weekend news briefly gave a 10 percent bump to the stock price of Puma Biotechnology (NASDAQ: PBYI), which has a next-generation HER2-positive breast cancer treatment under FDA review. Puma shares ended the day more modestly, with a 2 percent gain.

Photo of Chicago skyline by Tony Webster via Creative Commons.