History repeated itself for Agenus Inc. six months after Glaxosmithkline plc’s (GSK) phase III DERMA trial of its MAGE-A3 cancer immunotherapeutic, formulated with Agenus’ QS-21 Stimulon adjuvant, missed its primary endpoint of extending disease-free survival (DFS) in melanoma. This time, the culprit was non-small-cell lung cancer (NSCLC). The phase III MAGRIT trial of GSK’s immunotherapeutic, known as zastumotide, missed both the first and second co-primary endpoints, failing to significantly extend DFS compared to placebo in either the overall MAGE-A3-positive population or in MAGE-A3-positive patients who did not receive chemotherapy.

As with the melanoma trial, GSK committed to continuing the study until an additional co-primary endpoint – designed to identify a subset of patients who may be more immunologically responsive – is reached.

Despite the double miss, investor reaction was a bit more tempered the second time around. Shares of Agenus (NASDAQ:AGEN) lost 50 cents, closing at $3.80. In contrast, the company’s stock tumbled 23 percent, dropping 87 cents to close at $2.84, following the melanoma miss. (See BioWorld Today, Sept. 6, 2013.)

GSK shares (NYSE:GSK) lost 69 cents on Thursday, closing at $54.02.

Officials at the pharma acknowledged disappointment but said the company remained committed to the effort to identify a subpopulation of NSCLC patients who might benefit from the cancer vaccine.

GSK remains blinded to the overall trial data from the analysis of the first two co-primary endpoints to allow for unbiased assessment of the third co-primary endpoint. The independent data monitoring committee (DMC) concluded that continuation of the trial to the third co-primary endpoint raised no specific safety concerns. Results from that analysis are expected next year.

The third co-primary endpoint, based on gene signature and designed to prospectively identify MAGE-A3 patients who might benefit from treatment, was a pre-defined criterion discussed prior to the trial with regulatory authorities, according to both companies. If analysis shows that DFS was met in the predefined subset, regulatory filings could follow.

To assess those findings, an independent third party is generating a mathematical model in a proportion of the data, known as the training set, according to GSK spokeswoman Melinda Stubbee. Once that effort is completed, GSK will have access to information about the training set but not to patient-level data. GSK will gain access to the remainder of the MAGRIT data following completion of testing on the training set or at a time recommended by regulatory authorities.

Stubbee said GSK plans eventually to publish the MAGRIT data and present the findings at a medical conference.

Opened for enrollment in October 2007, the randomized, double-blind, placebo-controlled MAGRIT trial is evaluating the efficacy and safety of GSK’s MAGE-A3 cancer immunotherapeutic in stage IB, II and IIIA completely resected NSCLC patients whose tumors expressed MAGE-A3 – an antigen expressed in a variety of cancers but not in normal cells. In NSCLC, MAGE-A3 is expressed in approximately one-third of tumors in patients diagnosed with stage IB-IIIA disease.

MAGRIT enrolled 2,312 MAGE-A3-positive patients across more than 400 sites in 34 countries, with patients given up to 13 intramuscular injections of either the MAGE-A3 immunotherapeutic or placebo over 27 months. The MAGE-A3 cancer vaccine candidate consists of recombinant MAGE-A3 protein and the immunostimulant AS15 – a combination of the QS-21 Stimulon adjuvant, monophosphoryl lipid A and CpG7909, a TLR-9 agonist, in a liposomal formulation.

QS-21 Stimulon was licensed from Antigenics Inc., a wholly owned subsidiary of Lexington, Mass.-based Agenus.

In addition to the co-primary endpoints, MAGRIT is evaluating secondary endpoints of overall survival, health-related quality of life and safety.

GSK also continues to evaluate in the phase III DERMA study whether a gene signature can identify a subpopulation of melanoma patients that would benefit from zastumotide. GSK said work is progressing on the mathematical model to allow assessment of DFS in the gene signature population, the second co-primary endpoint in that study, with findings also due to report next year.

In September, following the miss in melanoma, Agenus Chairman and CEO Garo Armen told BioWorld Today that the DMC’s decision to continue the DERMA trial suggested that committee members may have seen an encouraging trend despite missing DFS in the overall population.

“If there was a signal in the melanoma trial in much later-stage patients, we believe chances are the signal may be much more robust in the lung trial which has enrolled twice the number of patients . . . in earlier stages of disease,” Armen said.

Agenus officials did not respond to interview requests.

AGENUS A ‘TABLE-POUNDING BUYING OPPORTUNITY’?

Despite their promise, cancer immunotherapies have been a tough nut to crack, as Dendreon Corp. ruefully learned from prostate cancer vaccine Provenge (sipuleucel-T) – the first approval in the space. Since the FDA green-lighted Provenge in April 2010, the company has fought the Centers for Medicare & Medicaid Services over coverage of the drug and investor disappointment over lackluster sales. (See BioWorld Today, April 30, 2010, July 2, 2010, Nov. 19, 2010, Aug. 5, 2011, and Nov. 4, 2011.)

Even after the European Commission granted marketing authorization for Provenge last year, analysts were underwhelmed about its prospects. (See BioWorld Today, Sept. 18, 2013.)

In the meantime, Dendreon’s shares (NASDAQ:DNDN) have plummeted from a high of $57.67 following FDA approval of Provenge to close Thursday at just $3.

Competitor Yervoy (ipilimumab, Bristol-Myers Squibb Co.), approved in 2011, has so far enjoyed better success, and other cancer immunotherapies are slowly making their way through the clinic. Candidates from companies such as Amgen Inc., Northwest Biotherapeutics Inc., Newlink Genetics Corp., Aduro Biotech Inc., Transgene SA, Celldex Therapeutics Inc., Immune Design Corp., Gradalis Inc. and Curevac GmbH continue to progress, and newcomers like Jounce Therapeutics Inc. and Juno Therapeutics Inc. have added excitement. (See BioWorld Today, Sept. 19, 2012, Feb. 14, 2013, May 16, 2013, Oct. 31, 2013, Dec. 3, 2013, Dec. 5, 2013, Jan. 10, 2014, Jan. 15, 2014, and March 10, 2014.)

In all, more than 400 trials of cancer immunotherapies are under way in solid and hematologic cancers, according to Thomson Reuters Cortellis Clinical Trials Intelligence.

But the space has been dented by a number of misses, including those at Immunocellular Therapeutics Ltd., Prima Biomed Ltd., Vical Inc., Peregrine Pharmaceuticals Inc. and Oncothyreon Inc. (See BioWorld Today, Dec. 20, 2012, June 28, 2013, Aug. 13, 2013, Sept. 19, 2013, and Dec. 13, 2013.)

GSK, of course, is not a one-trick pony, and neither is Agenus. In December, the biotech reported findings from a phase II study showing that more than 90 percent of recurrent glioblastoma multiforme patients treated with its Prophage Series G-200 were alive six months after surgery, and 30 percent survived 12 months, with median overall survival of 11 months. The Prophage Series G-200 is a patient-specific heat-shock protein-based therapeutic vaccine. (See BioWorld Today, Dec. 17, 2013.)

Agenus also is advancing its checkpoint antibodies in a handful of indications, including cancer, viral infections, autoimmune disease and inflammation. Initial investigational new drug filings are expected next year.

With those additional assets in mind, H.C. Wainwright & Co. analyst Reni Benjamin played devil’s advocate on Agenus, calling the second zastumotide miss a “table-pounding buying opportunity.” Benjamin reiterated a “buy” rating and 12-month target price of $8 for Agenus, noting the company is already shifting its corporate focus toward the checkpoint inhibitors.

“With a portfolio of diverse assets, a confluence of milestones anticipated over the next 12-18 months, and a cash position of $80 [million], we believe Agenus represents an undervalued player in the immuno-oncology space,” Benjamin wrote, noting the first of six preclinical checkpoint molecules could begin to move into the clinic in the second half of next year.

“Going forward, if the checkpoint pipeline is successful, we expect Agenus to secure [a] partnership or get acquired,” he added.