The 50th anniversary meeting of the American Society of Clinical Oncology (ASCO) starts tomorrow in Chicago, where attendees will examine data from more than 2,900 abstracts chosen for oral presentation, clinical science symposia or posters.

A record 5,530 abstracts were submitted this year. As in 2013, immuno-oncology is expected to show strong at the meeting, with particular interest in the PD-1/PD-L1 pathway. Spotlighted compounds include New York-based Bristol-Myers Squibb Co.'s (BMS) nivolumab and Merck & Co. Inc.'s MK-3475, more commonly known as pembrolizumab (formerly called lambrolizumab).

Merck, of Whitehouse Station, N.J., earlier this month completed its biologics license application filing for MK-3475, asking for approval to treat melanoma patients unsuccessfully treated with BMS' Yervoy (ipilimumab), an indication for which the FDA has granted it both breakthrough designation and priority review status. (See BioWorld Today, May 7, 2014.)

BMS' nivolumab, undergoing tests against non-small-cell lung cancer (NSCLC), has been in the news lately, too, by way of the deal with Celldex Therapeutics Inc., under which the pair will evaluate the compound with Celldex's CD27-targeting varlilumab. (See BioWorld Today, May 15, 2014.)

Less celebrated of late is another likely ASCO star: MPDL3280A, in development by Basel, Switzerland-based Roche AG's Genentech unit. The PDL1-blocking compound came onto the radar at last year's ASCO meeting because of a 171-patient phase I trial in solid tumors. (See BioWorld Today, May 16, 2013.)

MPDL3280A since has gained an impressive 50 percent response rate in PDL1-positive bladder cancers, and efficacy in PDL1-negative tumors will be offered at this year's ASCO. The percentage of patients with PDL1-positive tumors was not revealed in the abstract, but 10 of 20 patients were said to respond, including one complete response – an outcome that Leerink Partners LLC analyst Seamus Fernandez found "particularly positive," he wrote in a research report ahead of the meeting.

Evan Yu, an oncologist who specializes in genitourinary (GU) cancer, went further, deeming the results "incredibly impressive." An associate professor at the University of Washington School of Medicine, Yu spoke with Credit Suisse analysts during a hosted call Wednesday. Bladder cancer, he said, is "probably the next area in GU oncology to explode."

Patients who have already progressed on platinum-based chemotherapies, unlike those with testicular cancer ("easily cured") or prostate cancer (who "live for years and years"), usually do not survive long, Yu said. Other PDL-1 therapies have targeted melanoma, lung and renal cell cancer, so bladder is "a good niche to match up," he added.

Finding the PDL1-negative patients is important, Yu said. "I'm very curious, because I know that the company has data in lung cancer that seems to show PDL1-positivity does seem to matter in terms of response rates. There are big question marks in the field whether these drugs should be developed just for those positive patients or in the grand scheme for all patients," he said.

To sort PDL1-positive from PDL1-negative patients is not like identifying HER2-positive breast cancer patients. "At some point, [drug developers] need to think about doing some sort of directed biomarker approach," Yu said. "There's more and more data arising to show that the patients who respond the best have tumors that are very mutagenic," such as lung and melanoma. "Bladder cancer is probably fourth or fifth on the list," Yu said. "You're probably targeting multiple different antigens, and it's worthwhile for them to consider what some of those major antigens might be and start looking at peripheral immune response in some of these patients."

CHEMO SYNERGY UNLIKELY

Nailing down biomarkers will grow increasingly important, Yu said. "Institutional review boards are all over us if we try to do selective therapy based on a non-clear certified test by saying, 'We're going to do the immunohistochemistry, and if it's positive, we're going to then select the patients; if it's negative, sorry, they screen-failed.' That is becoming a thing of the past."

Safety with MPDL3280A "looks pretty good – fatigue, nausea, the classic kind of stuff that you might expect to see," Yu said. Next comes a much-larger phase II trial. "It's a smart design," he said, with 330 patients, including 300 second-line or worse and 30 treatment naïve. Some immunologists have suggested that those who have been through treatment already might do better with such therapies than new patients. "It might be challenging for an open-label trial like this to be a true registrational trial, but you never know."

Toxicity will be watched especially close in the phase II trial, Yu said. If it's mild, other patients might "come out of the woodwork," having given up hope, and other zones of bladder cancer could open up, such as patients with earlier-stage disease or those who need maintenance therapy. "The pie, for various reasons, could be larger than one anticipates," he said.

Trying the compound in combination with chemotherapy would likely be futile. "The problem is that it's a bit of guesswork," Yu said, since there are no good chemotherapies available in second-line treatment, although taxanes and pemetrexed have been tried. "If you had to do a randomized phase III trial, you could just go [with] a PDL-1 inhibitor vs. a taxane," he said. "[Or] you could do taxane plus a PDL1 inhibitor vs. a taxane, but I personally don't feel that's necessary." Unless a "true synergism" is found between the chemotherapy and the PDL-1 drug, the scenario should be avoided, Yu said. "If you're not sure that it's even additive, then why would you set yourself up for that competition?"

MPDL3280A is also undergoing tests in combination with the vascular endothelial growth factor-targeting antibody Avastin (bevacizumab), also from Roche's Genentech unit, in tumor types that include NSCLC and renal cancer.

The ASCO meeting runs through Tuesday.