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Genentech’s onartuzumab fails in phase III trial for non-small-cell lung cancer

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By Marie Powers
Staff Writer

Roche AG unit Genentech Inc. said it was halting the phase III METLung study of onartuzumab, or Metmab, in combination with Tarceva (erlotinib, Roche and Astellas Pharma Inc.) in MET-positive, advanced non-small-cell lung cancer (NSCLC) on the recommendation of an independent data monitoring committee after a planned interim analysis showed the drug did not meet its primary endpoint of overall survival (OS).

The company said adverse events were similar in both study arms – one with the combination and the other with Tarceva alone.

The failure in NSCLC, the drug’s lead indication, is a blow to Genentech but even more of a disappointment for the indication. NSCLC accounts for some 85 percent of lung cancers but has limited treatment options in advanced stages, when most patients are diagnosed. A monoclonal monovalent, or one-armed, antibody, onartuzumab was designed to inhibit MET signaling in cancer cells by binding to the extracellular domain of MET, thus blocking HGF-mediated activation.

Despite the company’s palpable disappointment, spokeswoman Krysta Pellegrino said Genentech remains committed to developing next-generation drugs for NSCLC, beyond the approved therapies Tarceva and Avastin (bevacizumab).

“This doesn’t end here for Genentech,” Pellegrino told BioWorld Today. “We’re going to continue to try to tackle this really difficult disease.”

The randomized, double-blind METLung study was evaluating efficacy and safety in patients with second- or third-line advanced NSCLC identified as MET-positive. METLung randomized 499 patients to 150 mg of Tarceva daily plus either 15 mg/kg of onartuzumab or placebo every three weeks, both administered intravenously. In addition to the primary endpoint of OS, secondary endpoints included progression-free survival (PFS), objective response rate and safety.

Pellegrino declined to provide additional details, noting that South San Francisco-based Genentech is evaluating the results more fully to determine what impact the findings might have across the onartuzumab clinical program, which includes a second phase III study in patients who are MET-positive and EGFR-positive and an ongoing phase III in metastatic HER2-negative gastric cancer.

“We still have to take a deeper diver into the data,” she said.

Genentech plans to submit data from the METLung study for presentation at an undisclosed medical meeting.

The compound also is in earlier studies in metastatic colorectal cancer, Avastin-naïve recurrent glioblastoma and triple negative metastatic breast cancer. All told, Roche/Genentech has 13 trials of onartuzumab under way, according to Thomson Reuters Cortellis Clinical Trials Intelligence (CTI).

Pellegrino acknowledged the trial failure was a surprise because the study was conducted on the basis of phase II findings that showed significant improvement in OS and PFS for MET-positive patients treated with the onartuzumab/Tarceva combination compared with Tarceva alone.

“We believe there was scientific rationale” for the phase III, she said.

METLung was designed using immunohistochemistry, or IHC, to stratify patients by MET expression and by EGFR-activating mutation status. Pellegrino declined to confirm whether Genentech will seek to uncover a subset of responders from the overall patient population, using IHC or other biomarkers.

“Looking at the entire, overall MET population, there was no benefit in overall survival, so that’s why we’re stopping the study,” she said.

Only a minority of tumors are ‘addicted to MET’

Fine-tuning the patient population to seek a path forward for onartuzumab in NSCLC would not be an unprecedented strategy. In October 2013, Arqule Inc. reported data at the European Cancer Congress in Amsterdam suggesting its oral MET inhibitor, tivantinib, might have an opportunity in NSCLC, after that drug also missed OS in a phase III study a year earlier. (See BioWorld Today, Oct. 3, 2012, and Oct. 1, 2013.)

In evaluating the subset of data on tivantinib, partnered with Tokyo-based Daiichi Sankyo Co. Ltd., RBC Capital Markets analyst Adnan Butt suggested Arqule could lay “the groundwork for a potential path forward in [a] biomarker-identifiable population for non-small-cell lung cancer patients with high c-MET expression, which would be upside to expectations.”

In a flash note following the onartuzumab phase III disclosure, Leerink Partners LLC analyst Michael Schmidt noted that Exelixis Inc. and Mirati Therapeutics Inc. are developing MET-targeting multi-kinase inhibitors with “significantly different” strategies in NSCLC.

“MRTX and EXEL plan to test MGCD-265 and cabozantinib respectively in NSCLC patients harboring certain ‘driver mutations’ representing a much smaller patient subset with a stronger scientific rationale, in our view,” Schmidt wrote. “In addition, cabozantinib and MGCD-265 are differentiated from MetMab in that they are multi-kinase inhibitors also inhibiting additional kinases implicated in various cancers. MET inhibition with multi-kinase inhibitors thus remains a valid strategy in certain indications in our view.”

Cabozantinib, branded Cometriq, was approved by the FDA in November 2012, and Exelixis since has pursued an expanded label for the inhibitor of MET, VEGFR2 and RET. (See BioWorld Today, Nov. 30, 2012.)

Schmidt maintained that MET, as a single target, is a tough nut to crack.

“Although almost all major human cancers seem to harbor some dysregulation of the MET pathway, only a minority of tumors are ‘addicted to MET,’ explaining in our view the mixed clinical results seen thus far with MET inhibitors when studied in broader patient populations,” he wrote.

That challenge hasn’t daunted other big guns in the MET inhibitor space, which include Amgen Inc. with AMG-208 along with big pharmas Eli Lilly and Co., Pfizer Inc., EMD Serono, Glaxosmithkline plc and Novartis AG, partnered with Incyte Corp. on cancer drugs in a deal that could top $1 billion. (See BioWorld Today, Nov. 30, 2009, Dec. 22, 2010, and Nov. 17, 2011.)

In the meantime, Genentech has other tricks in its NSCLC bag, including a just-opened phase III study of investigational immunotherapy anti-PDL-1 in 850 patients, with OS as the primary endpoint and secondary endpoints of PFS, duration of response, adverse events and overall response rate. The study, which is using a companion diagnostic to identify PDL-1-positive patients, is expected to take four years to complete, according to Cortellis CTI.

Parent company Roche also is studying the ALK inhibitor alectinib, which has FDA breakthrough therapy designation in NSCLC.