Cancer in the crosshairs: ASCO brings fresh ideas, data jubilee across types

CHICAGO – No one was surprised to see immune-based therapies taking much of the air time at this year's American Society of Clinical Oncology (ASCO) meeting, since they've dominated the key scientific powwow in cancer for several years, and a fountain of outcomes showed that targeted drugs, in combination regimens as well as single agents, still have plenty going for them.

"Everyone is here, the world is here," said ASCO President Peter Yu on the first day of the five-day meeting, which drew about 35,000 people to Chicago and made hotel reservations hard to find.

In immunotherapy, Bristol-Myers Squibb Co. (BMS) maintained a high profile with trial results for Opdivo (nivolumab), cleared by the FDA in March for squamous non-small-cell lung cancer (NSCLC) – the first immunotherapy to win FDA approval for lung cancer. New data showed the drug can also provide significant benefit to patients with the more common, nonsquamous form of NSCLC, especially those with tumors that express high levels of tumor programmed death-ligand 1 (PD-L1). On the first day of the ASCO meeting, BMS detailed findings from phase III Checkmate-057 study.

Opdivo shone, too, in a phases III study called Checkmate 067, which provided that the programmed cell death-1 (PD-1) inhibitor, cleared by the FDA late last year for melanoma, helped patients more than the firm's other approved melanoma drug, Yervoy (ipilimumab), in patients with previously untreated cases of the worst form of skin cancer not only when the two drugs were given together but also when Opdivo was given by itself. Checkmate 067 was the first late-stage experiment to compare a combination of immune checkpoint inhibitors with single-agent Yervoy, and ASCO attendees learned that Opdivo by itself more than doubled the average time to disease progression compared to Yervoy (6.9 months vs. 2.9 months), and the benefit jumped to 11.5 months with the combo regimen.

London-based Astrazeneca plc's biologics research and development arm, Medimmune, rolled out data showing clinical activity with manageable safety profiles for the anti-PD-L1 monoclonal antibody MEDI4736 as a monotherapy and in combination with other immuno-oncology and small-molecule therapies across different tumor types and tumor biology. Specifically, the MEDI4736/tremelimumab combo worked in phase Ib trials in PD-L1-positive and PD-L1-negative advanced NSCLC patients. Tremelimumab is a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal antibody. The pairing represents a dual-pronged approach of steadily increasing interest in cancer: stimulating the immune system to mount a response and keeping specific T-cell responses in play. (BMS' Yervoy also blocks CTLA-4 to get T cells revved up.) Astrazeneca, which bought Medimmune Inc. in 2007 for $15.2 billion, said the study established appropriate doses to move forward into phase III combination trials. (See BioWorld Today, April 24, 2007.)

In the open-label, dose-escalation trial, 63 patients with 16 weeks or more of follow-up were evaluable for clinical activity, and 102 patients were evaluated for safety. Results showed particular activity and tolerability in PDL-1-negative patients, who make up about 70 percent of NSCLC patients and who are less likely to respond to monotherapy. In the PD-L1-negative patient subset, overall response rate (ORR) was 27 percent (9/33) and disease control rate (DCR) – defined as complete response, partial response, or stable disease for 16 weeks or more – was 48 percent (16/33). Overall, almost half of patients in the study achieved a partial response or stable disease, with ORR of 27 percent (17/63) and DCR of 41 percent (26/63). Adverse events were described as manageable and generally reversible.

HAIL FELLOW WELL 'MET'?

Other intriguing, albeit early stage, results came from a study with Kenilworth, N.J.-based Merck & Co. Inc.'s PD-1 inhibitor Keytruda (pembrolizumab), as researchers found the first biomarker – mismatch repair (MMR) deficiency – that may foretell success with the approved cancer compound.

MMR deficiency means loss of function of the MMR pathway, which entails failure to repair replication-associated errors due to a defective MMR system, and lets mismatch mutations remain all over the genome, but especially in regions of repetitive DNA called microsatellites, which then leads to microsatellite instability. That's where cancer susceptibility enters the picture in the form of Lynch syndrome, which clinicians once referred to as hereditary nonpolyposis colorectal cancer syndrome.

Researchers have known for a while that MMR deficiency plays a role in cancer; it's one of the better characterized forms of gene abnormality in that regard. Data detailed at ASCO revealed that the marker's presence meant better outcomes across a range of cancers, and among those with colorectal tumors specifically, 62 percent of MMR-deficient ones shrank, while no responses appeared among MMR-proficient patients: those without the abnormality. Among MMR-deficient patients with noncolorectal cancers the response totaled 60 percent.

The MMR discovery was one of many that are turning cancer researchers' eyes toward the genetic characteristics of tumors rather than histology, even though clinical trials still are mainly focused on the latter, and where in the body the illness is located. Exploring such signals across solid tumors is the goal of the National Cancer Institute's MATCH (Molecular Analysis for Therapy Choice) trial, described as the largest, most rigorous precision oncology trial in history, disclosed at ASCO. Investigators will sequence the DNA of 3,000 patients and enroll 1,000 patients in a number of treatment groups.

Another research effort that drew attention is one – the first – designed by ASCO itself: the TAPUR (Targeted Agent and Profiling Utilization Registry) study, which will gather data on the efficacy and toxicity of targeted cancer drugs on the market for a variety of oncology types, including advanced solid tumors, multiple myeloma and non-Hodgkin's lymphoma. On board to provide drugs that patients in the regulator-cleared experiment may be prescribed off-label based on the characteristics of their disease are Pfizer Inc., Roche AG unit Genentech, Eli Lilly and Co., Bristol-Myers Squibb Co. and Astrazeneca plc.

Precision medicine via biomarkers could be fueled by such discoveries as that made by Cambridge, Mass.-based Foundation Medicine Inc., which disclosed while the ASCO meeting was under way new data showing the role of MET exon 14 alterations as drivers of growth of NSCLC. The analysis showed that the MET exon 14 alterations occurred in more than 3 percent of NSCLC and identified patients who derived meaningful clinical benefit from treatment with MET-targeted therapies. Adding METex14 alterations to the growing list of oncogenic drivers in NSCLC, Foundation said, supports the need for broad reimbursement coverage of comprehensive genomic profiling.

MET science lay behind the early data from a phase I/Ib study with the targeted tyrosine kinase inhibitor MGCD265 in NSCLC, made known during the ASCO meeting. The outcome failed to enliven Mirati Therapeutics Inc.'s shares, but results suggest the drug is active and add weight to the precision-medicine hypothesis that fuels the work.

San Diego-based Mirati offered the results over the weekend, and Mirati's stock (NASDAQ:MRTX) closed Monday at $25.62, down $11.04, or 30 percent. Tuesday saw only a small revival, with shares ending at $26.58.

MGCD265 takes aim at tumors in patients with MET or Axl gene alterations. In the ongoing single-agent expansion study in NSCLC, Mirati found turned up regression in three patients (the first three selected from a total of 25 in the phase I trial), as well as improvement in clinical symptoms such as pain and shortness of breath. The compound is the first MET inhibitor targeting MET mutations, MET gene amplification and Axl rearrangements, which together comprise as much as 8 percent of NSCLC patients.

'JAK' OF THE PLATELET TRADE

The multinational study began at the end of last year and continues to enroll. Patients get 1,050 mg of the drug twice daily for 21-day cycles and are assessed for response after every second treatment cycle. So far, the first three patients with MET gene alterations showed a clinical benefit, including regression and improvement in clinical symptoms such as pain and shortness of breath, though the patients have not met RECIST criteria.

There's the rub. "While investors may have expected a larger sample set and may have expected some responses, we think the [outcome with the] first three patients offers evidence of drug efficacy," especially given how sick the patients were, in the view of Jefferies analyst Biren Amin. Each had a previously undergone five or six lines of therapy, and one had failed on a PDL-1 inhibitor.

Amin wrote in a research report that Wilmington, Del.-based Incyte Corp. has shown data from a phase I trial that tested INC280 in combination with Tarceva (erlotinib, Roche AG and Astellas Pharma Inc.) in 18 patients with MET-expressing NSCLC. Of the 16 patients for whom data were reported, one achieved a complete response with the rest showing stable disease. The patients enrolled were less severely ill, too, with three-quarters at an Eastern Cooperative Oncology Group performance status of zero, which means they were as functional as before they got sick. "In light of these data, it appears MGCD265 monotherapy is effective, and we think we would observe more robust efficacy in earlier lines of therapy which is the company's intent in a larger phase II trial," Amin wrote in a research report.

Piper Jaffray analyst Charles Duncan said Mirati's findings "exceeded our expectations in terms of responses and number of patients. Biomarker data suggest to the company that the [current dose] is achieving maximal inhibition of MET, based on prior results with other inhibitors." The phase II trial could start in the fourth quarter of this year, he wrote in a research report.

Less sanguine was Brean Capital Markets' Jonathan Aschoff, who pointed to differences between the ASCO abstract and what was actually presented at the meeting. "We note the strong recent pre-ASCO stock price surge and the current results lacking in RECIST criteria responses do not incline us to raise our target price to maintain a buy rating," he wrote in a report. "We are therefore downgrading Mirati to hold from buy."

Seattle-based CTI Biopharma Corp. and partner Baxter International Inc., of Deerfield, Ill., offered more results at ASCO from PERSIST-1, testing the next-generation JAK2/FLT3 multikinase inhibitor pacritinib in myelofibrosis (MF). The results were intended to better characterize the drug's position with regard to the marketed JAK2 inhibitor Jakafi (ruxolitinib), developed by Incyte and partner Novartis AG, of Basel, Switzerland. Lead study author Ruben Mesa, director of the Mayo Clinic Cancer Center in Scottsdale, Ariz., said the major differentiating factor for pacritinib – though there's been no head-to-head experiment – is the degree of efficacy and safety for patients with significant thrombocytopenia. The FDA first cleared Jakafi for MF based on beneficial changes in spleen volume, and later gave it the nod for polycythemia vera. Consensus forecasts estimate sales of $557 million for the year. Jakafi, though, is not for patients with thrombocytopenia, defined as patients with platelets counts either below 50,000 at baseline or those who fall below 50,000 while on therapy.

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