With eagerly awaited abstracts unleashed on the world from the American Society of Clinical Oncology (ASCO) annual meeting, pundits and investors were ransacking the batch for clues to success. ASCO unveiled no fewer than 5,000 studies from which results were to be offered at the cancer meeting, which starts in about two weeks.

Stock movers included Incyte Corp., Clovis Oncology Inc. and Newlink Genetics Corp., though it was not clear in every instance why shares moved up or down.

Immunotherapy, popular enough at this year's ASCO to have gained the acronym "IO," included abstracts that presaged satisfying results with such compounds as Incyte's oral indoleamine dioxygenase-1 (IDO) inhibitor INCB24360 when paired with the melanoma drug Yervoy (ipilimumab, Bristol-Myers Squibb Co.). The combination fell short of the overall response rate garnered by pairing Yervoy with BMS' nivolumab, however, sending Incyte shares (NASDAQ:INCY) down $4.95 to close Thursday at $50.95.

The PD-1 checkpoint inhibitor nivolumab, which has proven strong in squamous non-small-cell lung cancer (NSCLC), along with '360 had made news already because of separate deals to develop them as combo drugs. New York-based BMS signed an agreement with Celldex Therapeutics Inc., of Hampton, N.J., to test PD-1 checkpoint inhibitor nivolumab in NSCLC with Celldex's CD27-targeting varlilumab. Wilmington, Del.-based Incyte scored a pact with Medimmune, an arm of Astrazeneca plc, of London, to test the latter's anti-PD-L1 immune checkpoint inhibitor, MEDI4736, in combination with '360. in a phase I/II study in previously treated metastatic and recurrent NSCLC and other advanced or metastatic cancers. (See BioWorld Today, May 15, 2014.)

"I think [cancer immunotherapy] is very exciting and ultimately will be beneficial to patients, but I do think it's blocked out a little bit of the sun at ASCO again," said Ron Squarer, CEO of Boulder, Colo.-based Array Biopharma Inc., referring to a similar splash made at 2013's meeting.

Of Array's nine abstracts, Leerink analyst Michael Schmidt was most intrigued by the phase I/II combination data of MEK inhibitor binimetinib (MEK162) with LEE011, the CDK 4/6 inhibitor from Novartis AG, of Basel, Switzerland, in NRAS-mutant melanoma patients, which showed a response rate of 42 percent vs. 20 percent observed in the phase II trial with binimetinib alone. "This is, to our knowledge, the first data for the combination of a MEK inhibitor with a CDK 4/6 inhibitor in NRAS-mutant melanoma patients," Schmidt wrote in a research report. Wells Fargo analyst Brian Abrahams was more circumspect, allowing that "limited safety data suggest a reasonable tolerability profile. While these are promising data, longer-term the question is how does this combination benefit Array when MEK162 is returned by Novartis to Array?"

It seems likely. Novartis in April acquired for $16 billion the oncology portfolio of London-based Glaxosmithkline plc, which contains the MEK inhibitor Mekinist (trametinib), approved by the FDA in January for use in combination with GSK's Tafinlar (dabrafenib) for the treatment of patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations.

"There is language in the contract [with Novartis] related to exclusivity on a MEK," Squarer told BioWorld Today, adding that it "would be a challenge to imagine a scenario in which they would keep two MEK inhibitors. There would be certainly [regulatory] scrutiny about them having both." Mekinist is already on the market, "and we're assuming they're favoring an on-market product vs. one that is to be filed according to them in 2015," Squarer said.

MEK'ING IT WORK

"Certainly, there's nothing wrong with binimetinib," he said, as ASCO abstracts will show. Three pivotal trials are under way, with 20 more experiments at various other stages. In the study with LEE011, the new data "point to essentially a doubling of response rate, about 43 percent," Squarer said. "We're starting to see very exciting results in what has been historically a very unresponsive tumor. Then the question is, how about the durability?" That question has yet to be answered.

Binimetinib and Array's other MEK inhibitor, selumetinib, partnered with London-based Astrazeneca plc, may find their places with immunotherapy. "We have allowed patients with prior immunotherapy to be recruited into our studies," Squarer noted. The first question will be whether adding a MEK inhibitor after immunotherapy turns out to have benefit.

"Longer term, frankly, we're going to have to determine if MEK inhibitors should be used before immunotherapy, in combination with immunotherapy or after," Squarer said. "The worst case, from a commercial-value point of view, would be after." But the best case could come to pass instead. "Patients who respond to immunotherapy tend to have very durable responses, but cures are very rare, so you're going to be getting patients a little bit later," he pointed out. "If there's utility in combining a MEK with immunotherapy, then you're talking about patients benefiting from MEK inhibitors for a much longer period than we imagined as we were developing the franchise."

The Astrazeneca deal is "more of a straight license than with Novartis," Squarer said, and Astrazeneca has an immunologic agent in its portfolio, too. The firm is focused on NSCLC, but is doing pivotal trials in melanoma of the eye and thyroid cancer as well. "We would be very surprised if they're not going to be doing exploratory work with their immunologic and selumetinib [combined]," Squarer said.

Also in the ASCO abstract parade, Boulder, Colo.-based Clovis Oncology Inc. scored with CO-1686, an oral, targeted covalent inhibitor of mutant forms of the epidermal growth factor receptor for NSCLC. Leerink Partners LLC analyst Marko Kozul wrote in a research report that data to be detailed during the meeting "reinforce a superior tolerability profile for CO-1686 in a meaningful but small number of lung cancer patients." The compound could yield data from the phase II expansion cohort later this year, and a regulatory submission might happen in the middle of next year. Clovis' stock (NASDAQ:CLVS) closed Thursday at $59.25, up $8.16, or 16 percent.

Something of a paradox was Newlink Genetics Corp., of Ames, Iowa, which in March offered an encouraging interim look at phase III data from its phase III IMPRESS trial of algenpantucel-L in patients with surgically resected pancreatic cancer. The firm disclosed, without details, nine abstracts to be presented at ASCO. Newlink shares (NASDAQ:NLNK) sank 3.50, or 13.6 percent, to close at $22.20.

In other news ahead of the ASCO meeting:

Cornerstone Pharmaceutical Inc., of Cranbury, N.J., said data from a phase I trial with its first-in-class CPI-613 in patients with relapsed or refractory acute myeloid leukemia will be offered in a poster session that suggests the compound in combination with high dose ara-C and mitoxantrone is a promising salvage therapy regimen, especially in older patients and those with high-risk disease.

Eli Lilly and Co., of Indianapolis, has a poster on abemaciclib, an oral drug administered twice daily, showing single-agent activity in patients with advanced non-small-cell lung cancer (NSCLC) in a phase I study. Enrolled were 57 patients with advanced NSCLC who progressed or relapsed after standard treatments. The patients received a median of four prior regimens, and 29 patients had KRAS mutations while 24 were KRAS wild-type. KRAS status was unknown for four patients. Patients received abemaciclib twice daily. Disease control rate – defined as patients demonstrating either a complete response, partial response or stable disease – was 49 percent for patients on abemaciclib, including two partial responses and 26 patients with stable disease. Consistent with preclinical data, the disease control rate was higher for patients with KRAS mutant type (55 percent) vs. those with KRAS wild-type (38 percent).

Merck KGaA, of Darmstadt, Germany, disclosed new biomarker findings from a retrospective analysis of the completed phase III CRYSTAL study that compared Erbitux (cetuximab, Eli Lilly and Co.) plus FOLFIRI with FOLFIRI alone. The analysis to be presented in detail involved a subgroup of patients with KRAS wild-type (exon 2) metastatic colorectal cancer (mCRC). A significant clinical improvement was observed in patients with RAS wild-type tumors when Erbitux was added to FOLFIRI in first-line mCRC. In this new analysis, 430 of 666 patients' (65 percent) tumor samples with wild-type KRAS (exon 2) status were assessed for additional RAS mutations (defined as mutations in exons 3 or 4 of KRAS and/or exons 2, 3 or 4 of NRAS). Of those, 367 were RAS wild-type, while 63 presented a mutation. The analysis shows a 27.7 percent increase in response rate, a three-month increase in median progression-free survival, and an 8.2-month increase in median overall survival in mCRC patients with RAS wild-type tumors (n = 367) receiving first-line Erbitux plus FOLFIRI, compared with patients receiving FOLFIRI alone.

Northwest Biotherapeutics Inc., of Bethesda, Md., provided an initial patient case study, showing signs of tumor necrosis (tumor death) and initial tumor regression from the company's ongoing DCVax-Direct trial for all types of inoperable solid tumors. The company plans to announce further case study information before the ASCO conference, while it continues collecting data from the trial. Although the trial is still at an early stage, with many of the patients only part of the way through the treatment regimen, the company also plans to provide overall information about the data to date by the time of the meeting. The specific case study just disclosed involves a sarcoma patient with a large tumor mass and multiple inoperable metastatic tumors in the lung.

Oncomed Pharmaceuticals Inc., of Redwood City, Calif., will highlight several studies. A phase Ia single-agent study of Fzd8-Fc enrolled 26 patients with advanced refractory solid tumors into seven dose-escalation cohorts to determine safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy. Fzd8-Fc was well tolerated up to 20 mg/kg every three weeks, double the estimated target efficacious dose based on PK and preclinical efficacy data. Fzd8-Fc-related adverse events (AEs) were mild to moderate (grades 1 and 2) and manageable, including dysgeusia (altered taste), decreased appetite, fatigue, muscle spasms, nausea and vomiting. One related grade 3 AE of increased blood phosphorus was reported. PD modulation of Wnt pathway genes was observed starting at 2.5 mg/kg. Doubling of β-CTX, suggesting increased bone turnover, was predominantly seen at higher dose levels and was reversible with zoledronic acid. Of 26 evaluable patients, eight experienced prolonged stable disease with tumor assessments for 112 days or longer on the study. Tumor indications with prolonged stable disease include pancreatic, renal cell, testicular, thyroid, non-small-cell lung cancer, as well as desmoid tumors and basal cell carcinoma. The compound is a first-in-class fusion protein that inhibits a key signaling pathway in cancer, the Wnt pathway. Fzd8-Fc selectively binds Wnt ligands that are activators of Wnt signaling.

Pharmacyclics Inc., of Sunnyvale, Calif., will feature Imbruvica (ibrutinib) in 10 abstracts, including both company-sponsored research studies and investigator-sponsored studies. Included is an oral presentation of long-term ibrutinib follow-up of three years, showing how single-agent Imbruvica achieved durable responses in patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, including those with deletion 17p, as independently confirmed.

Plexxikon, of Berkeley, Calif., a member of the Daiichi Sankyo Group, will highlight proof-of-concept phase I extension data with PLX3397 in pigmented villonodular synovitis (PVNS), a type of rare, often locally aggressive, musculoskeletal neoplasm that arises from the soft tissues of joints and tendons. Interim data from this ongoing trial showed that all evaluable patients treated with PLX3397 achieved either partial responses or stable disease. PLX3397 is an oral small molecule that potently and selectively inhibits CSF1R, KIT and oncogenic FLT3 kinases. CSF1R, in particular, has been shown to be a primary driver in PVNS. The data come from a study in solid tumors that enrolled 23 advanced PVNS patients who received at least one dose at the time of the interim analysis. Of the 14 patients with evaluable MRI scans, 11 patients (79 percent) achieved partial responses and three patients (21 percent) had stable disease as assessed by a novel scoring method to measure PVNS tumor volume. Mean tumor size reduction was 61 percent. For the 23 enrolled patients, the most common treatment-related side effects were hair color changes, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting and decreased appetite.

Provectus Biopharmaceuticals Inc., of Knoxville, Tenn., will feature its investigational (IL) agent PV-10 for intralesional treatment of locally advanced cutaneous melanoma. Abstracts showed that IL PV-10 can potentially offer cancer patients control of their cutaneous symptoms and can elicit a systemic antitumor immune response that may lead to response of uninjected lesions (the "bystander effect" that has been observed in prior clinical studies of PV-10), the company said. Researchers studied the safety and efficacy of IL PV-10 in an 80-patient international, multicenter, single-arm phase II trial. A subgroup analysis of 28 patients with all existing melanoma lesions injected and an additional 26 patients with only two uninjected bystander lesions showed that these patients experienced an exceptionally high rate of response. The best overall response rate in the 28-patient all-treated subgroup was 71 percent, with 50 percent complete response. Among the 54 patients in both subgroups (i.e., patients who had all of their disease monitored in the study), complete response (CR) was achieved in 232 of 363 injected lesions (64 percent). Furthermore, CR was achieved in 121 lesions after a single injection of PV-10; 84 lesions required two injections to achieve CR; 22 lesions required three injections; and five lesions required all four allowed injections.

Zeltia SA, of Madrid, Spain, will have new data with Yondelis (trabectidin) and PM1183. For the latter, a phase II trial was conducted with the compound as monotherapy to treat patients with platinum-resistant/refractory ovarian cancer, compared with standard treatment with topotecan. The primary endpoint, which was attained, was to determine the overall response rate, which was found to be higher, in statistically significantly terms, than that obtained with topotecan. The drug was also found to have an acceptable and manageable safety profile. With Yondelis, a phase II study comparing it and best supportive care in patients with translocation-related sarcoma (TRS) enrolled 76 patients. The primary endpoint was to evaluate the efficacy of both treatments by comparing progression-free survival (PFS). Both PFS and overall survival improved notably with Yondelis in patients that had been pretreated with other options available for TRS, the company said.