Merck's Phase III Tecemotide Vaccine Trial in NSCLC in Asian Patients Could Show Benefit, but ..

• Marginal OS benefit found in Asian patients in previous trial lends optimism

• Vaccine combination with PD1/PDL-1 checkpoint inhibitors promising

• Minimal side-effect profile encouraging for patients with Stage III lung cnacer

Merck (ETR:MRK) and Oncothyreon’s (NASDAQ:ONTY) Phase III tecemotide (L-BLP25 liposome vaccine) has the potential to demonstrate efficacy in an Asian non-smallcell lung cancer (NSCLC) population subset, oncologists said. Concurrent chemotherapy and radiation may contribute to positive outcomes, some noted. However, the justification for specifically testing this population is unclear, they noted.

The 500-patient INSPIRE trial (NCT01015443) is expected to have interim results in 2H14, according to analyst reports. The study compares BLP25 liposome vaccine, formerly known as Stimuvax, plus best supportive care to a placebo IV infusion and best supportive care. Subjects are only East Asian with Stage III, unresectable NSCLC who have demonstrated either stable disease or objective response following primary chemoradiotherapy, according to ClinicalTrials. gov.

There is another Phase III tecemotide trial, START2 (NCT02049151), which began in March 2014 with a recruitment goal of 1,002 patients, according to ClinicalTrials.gov. The inclusion criteria is the same as the INSPIRE trial, with no sites listed in East Asia. The estimated completion date is July 2018.

The sponsors declined to comment.

START data in Asian patients encouraging

A “reasonable chance” exists that INSPIRE will statistically meet the overall survival (OS) primary endpoint, principal investigator Dr Tony Mok said. He pointed to a marginal benefit found in OS for Asian patients from the earlier, Phase III START trial (NCT00409188), which ended in 2012 after it failed to show statistically significant OS in 1,513 patients.

Mok noted that targeting epidermal growth factor receptor (EGFR) mutation, which is found more often in the Asian population, has led to positive outcomes in past NSCLC trials. He cited AstraZeneca’s (LON:AZN) IRESSA (gefitinib) as an example.

EGFR mutations are found in about 30% of unselected NSCLCs in East Asian patients and in about 10% of North American and European patients (J Clin Oncol. 2013 Mar 10; 31(8):1070- 80).

The START data supports BLP25 liposome vaccine’s potential to show benefit in Stage III lung cancer patients and “nothing else out there” has similar strong data, said START investigator Dr Charles Butts, medical oncologist, Cross Cancer

Institute, Edmonton, Canada, said. If FDAapproved, the treatment would provide an option for Stage III NSCLC patients where none exists, he added. His caveat though was the INSPIRE trial’s sample size seems small.

To his knowledge, previous studies have not shown correlations between EGFR-mutated lung cancer patients and better outcomes with immunotherapy vaccines, said Dr Hak Choy, chair, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas. The rationale behind targeting only Asian patients is unclear, he added, with Bazhenova agreeing it was too early to tell.

Chemotherapy and radiation combination possibly beneficial

The best OS outcome from the START trial appeared to be in a subset of patients who received concurrent chemotherapy and radiation, rather than those who received the treatments sequentially, said lung cancer investigator Dr Lyudmila Bazhenova, medical director, University of California San Diego Moores Cancer Center. Patients who had the concurrent treatment had a median overall survival of 30.8 months compared with 20.6 months in the control arm (Lancet Oncol. 2014 Jan;15(1):59-68).

INSPIRE uses 918 micrograms in eight onceweekly consecutive subQ vaccinations, followed by one vaccination every six weeks until disease progression or if the patient discontinues the trial. START and START2 use 806 micrograms. In all three trials, patients receive one 300mg/m2 infusion of the chemotherapy cyclophophamide three days before the first BLP25 liposome vaccination.

This low chemotherapy dose is thought to stimulate immune cells and growth factor cells, Mok, a professor in the Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, said. But it is not yet known if this pretreatment makes a difference in clinical outcomes, he added.

The pretreatment administration could be important to help overcome resistance mechanisms that the tumor uses to avoid immune recognition, Butts said. The differences in chemotherapy doses are probably negligible because they are based on how the syringe is filled, he said.

PD1/PDL-1 checkpoint inhibitor drug combos, safety profile hopeful

Even if the INSPIRE trial fails to meet its primary endpoint, the vaccine may still be useful when combined with PD1/PDL-1 checkpoint inhibitor drugs, said lung cancer investigator Dr Karen Reckamp, co-director, Lung Cancer and Thoracic Oncology Program, City of Hope, Duarte, California. Some effector memory T cells may not be activated by the vaccine because the lung tumor has immune checkpoint blockages, for example, she said.

Lung cancer is not one disease and agents like immunotherapy may need “a sort of adjuvant” like checkpoint inhibitors, said Reckamp, who worked as an investigator on GlaxoSmithKline’s (LON:GSK) MAGE-A3 vaccine trial in earlier stage, resectable NSCLC. Much interest still exists in combining different immunotherapies with drugs having different mechanisms of action, Bazhenova agreed

The vaccine’s low toxicity is especially important for lung cancer patients who have emerged from highly toxic chemotherapy and radiation treatments, Butts said. So far only minor adverse effects have been seen on the skin at the injection site in the INSPIRE trial, said Mok. In general, the immunotherapy vaccines are very well-tolerated, Bazhenova agreed.

Merck’s market cap is EUR 26.8bn (USD 36.7bn). Oncothyreon’s market cap is USD 201.6m.

May 5, 2014

Kathleen Raven

Reporter

BioPharm Insight

Kathleen investigates oncology for BioPharm Insight. She previously worked as a journalist for Reuters Health and has written for Nature Medicine. Kathleen has a BA Honors in journalism, MS in ecology and MA in health and medical journalism, all from the University of Georgia.