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By Deena Beasley
CHICAGO, June 2 (Reuters) - Drugmakers includingBristol-Myers Squibb Co and Merck & Co aretesting which patients will most benefit from new cancertreatments based on a protein found in their tumors, but thatguide, known as a biomarker, may be too unreliable, researchersand health experts said.
Bristol's Opdivo and Merck's Keytruda are both therapiesdesigned to block a protein known as Programmed Death receptor(PD-1) that tumors use to evade the body's natural defenses.Competitors Roche Holding, AstraZeneca andPfizer also have similar drugs in an earlier stage ofdevelopment. The drugmakers are conducting clinical trials thattest patient tumors for a related protein called PD-L1.
The new drugs are mainly aimed at patients with so-calledsolid tumors suffering from diseases including lung cancer andliver cancer. Lung cancer, the most common type, claims 1.8million new cases each year worldwide. Sales of drugs to blockPD-1 could reach $33 billion a year by 2022, according toMorningstar.
New data published on Friday showed that Opdivo was mosthelpful to lung cancer patients with the highest levels of PD-L1in their tumors, adding to evidence of a link. That would suggest that doctors routinely test for the proteinbefore giving a patient Opdivo. The approach is already used forsome cancer drugs that are prescribed only if a patient has aspecific genetic mutation.
Cancer experts interviewed by Reuters at the AmericanSociety of Clinical Oncology meeting in Chicago, however, saidthat use of protein levels in a tumor as a guide for treatmentcannot be counted on in the same way as a genetic variation.
Test results can vary depending on which part of the tumorwas biopsied and the degree to which the cancer has spread. Inaddition, tests developed by drugmakers don't follow the samestandards.
So while clinical trials show that drugs like Opdivo andKeytruda work best in people who test positive for PD-L1, somepatients who test negative have benefited from the treatment.
"We shouldn't withhold immunotherapy from patients based ona biomarker yet," said Dr Roy Herbst, chief of medical oncologyat Yale Cancer Center in New Haven, Connecticut, referring toOpdivo. "We don't even know if PD-L1 is the right biomarker."
Dr. Richard Pazdur, the U.S. Food and Drug Administration'soncology chief, also cautioned that there is still a great dealof uncertainty about how to best measure for PD-L1.
"The key issue is whether the biomarker is essential forsafe and effective use of the drug," Pazdur said. "If not, thenit is probably not going to be an essential element in theindications for the drug. But it would be useful information."
WHO GETS A COSTLY DRUG?
Health insurers would also be keen to have a surefire testof when a novel, and expensive, cancer drug is most likely towork. Treatment with Opdivo or Keytruda alone costs about$12,500 a month in the United States, or $150,000 a year.
Pfizer's Xalkori, another new, expensive drug, is approvedby the FDA only for patients with a mutation of the ALK gene. Adiagnostic test must be used to identify the estimated 4 percentof patients with non-small cell lung cancer who are likely toimprove using Xalkori.
Current approvals for PD-1 drugs do not require tumortesting. Bristol's Opdivo, or nivolumab, was approved by the FDAin December to treat advanced melanoma. In March, it was clearedto treat a form of lung cancer, giving Bristol an earlyadvantage in the much larger market. Merck's Keytruda, orpembrolizumab, has been approved for advanced melanoma sinceSeptember and is awaiting approval as a lung cancer treatment.
Another confounding factor is that drugmakers are combiningOpdivo and Keytruda with other treatments to boost their effect,from well-established medications like chemotherapy toexperimental compounds.
In a small trial of patients with advanced lung cancer,AstraZeneca's experimental PD-L1 antibody, MEDI4736, was givenin combination with tremelimumab, which targets a differentimmune system inhibitor. Nearly half of patients who werenegative for PD-L1 responded to the treatment.
"It seems like the PD-L1 negative patients are nowresponding as well," said Bahija Jallal, executive vicepresident at AstraZeneca's MedImmune unit. "That was the wholepoint of doing the combination."
A Bristol-Myers trial found melanoma patients whose tumorscontained PD-L1 fared just as well with Opdivo alone as with acombination of Opdivo and a second immunotherapy, Yervoy. Butpatients without PD-L1 detected in their tumors lived more thantwice as long without their disease getting worse when treatedwith both drugs.
Around 80 percent of melanomas test positive for PD-L1,compared with around 50 percent of lung cancers, said EricRubin, Merck vice president, global clinical oncology. At thesame time, levels of PD-L1 are not static.
"If I check it today, it might change tomorrow. It might bedifferent in one area of the tumor than in another area," saidDr. Richard Carvajal, director of melanoma service at ColumbiaUniversity Medical Center in New York.
Drug companies are working to refine and standardize theirPD-L1 testing, as well as exploring other ways to identify whichpatients will benefit from immunotherapies.
Data presented at ASCO showed that Opdivo helped patientswith certain cancers, including colon cancer, whose tumorsexhibited an uncommon defect in genes needed for DNA repair. Drugmakers are also trying to discover if thereare any "negative" biomarkers to indicate which patients shouldnot be treated with immunotherapies.
"We are taking account of how the immune system isinteracting with the tumor. It's a completely different type ofbiomarker and understanding," said Sandra Horning, chief medicalofficer at Roche's Genentech unit. (Reporting by Deena Beasley; Editing by Michele Gershberg andJohn Pickering.)
