LONDON – Targovax ASA's plan to start a pivotal trial of its pancreatic cancer vaccine, TG-01, in the second half of 2018 has been derailed by the good news presented at the American Society of Clinical Oncology (ASCO) meeting last week that a new chemotherapy regimen extended overall survival for 20 months longer than standard-of-care gemcitabine.

The company was due to test TG-01, which is designed to elicit an immune response to tumors that express mutated RAS, in combination with gemcitabine in patients whose pancreatic tumors had been resected. But that standard of care is due to be rewritten, with the ASCO presentation of the Prodige study showing a dramatically improved effect of treating patients with modified FOLFIRINOX (folinic acid, fluorouracil [5FU], irinotecan, oxaliplatin).

The company's stock (OSV:TRVX) dropped 20.3 percent to close at NOK13.26 on Tuesday.

In the randomized phase III Prodige trial overall survival with FOLFIRINOX was 54.4 months, compared to 35 months with gemcitabine. (See BioWorld, June 5, 2018.)

"So the trial we envisaged would be with an obsolete standard of care – or if it was with FOLFIRINOX would take five to six years to complete," said Targovax CEO, Øystein Soug.

A new FOLFIRINOX median survival benchmark of close to five years means that a combination trial is not practically feasible for a small biotech like Targovax.

"We've had to take a step back and reassess what is the best way forward," Øystein said in a conference call held to discuss the situation.

Further compounding Targovax's difficulties in plotting a future clinical development pathway, the gemcitabine arm in the Prodige trial had longer overall survival, at 35 months, than was seen in the phase I/II trial of TG-01, at 33.4 months.

Putting a positive spin on the matter, Soug said it was fortunate the FOLFIRINOX data were presented at ASCO.

"It gave us the opportunity to reassess our trial design before committing to an inadequate combination treatment," he said.

Everything looked set fair for the pivotal trial of TG-01, after Targovax announced completion of the 32-patient phase I/II trial last month. Median overall survival in patients who received the vaccine in addition to standard-of-care gemcitabine was 33.4 months, compared to 27.6 months for gemcitabine alone.

Ninety-four percent of patients were alive one year after surgery and 72 percent two years after surgery. Ninety percent demonstrated mutant RAS-specific immune activation. Overall, the treatment was well tolerated.

Oslo, Norway-based Targovax has asked its scientific expert group to look at the Prodige trial and advise it how to proceed with TG-01. That will include investigating why Prodige showed better overall survival in the gemcitabine arm than the earlier ESPAC4 study, published in The Lancet in March 2017, against which Targovax benchmarked the performance of TG-01.

The question of why the gemcitabine arm performed so much better than would be expected, "was what people asked" as they came out of the Prodige session, said Magnus Jaderberg, CMO of Targovax, who was at ASCO. "It's important to understand if the patient population was different," he said.

However, he acknowledged, even if that was the case, the median overall survival in the FOLFIRINOX arm is "remarkable." And although there was some discussion at ASCO that the side effect profile of FOLFIRINOX was less favorable, with more patients dropping out due to toxicities, Jaderberg noted there was no difference between the two arms of Prodige in terms of the most severe grade 3 and grade 4 side effects.

FOLFIRINOX is already in use as first-line treatment for metastatic pancreatic cancer.

Can small biotechs keep pace?

With 30 percent of solid tumors expressing Ras, "there are clearly many opportunities," for TG-01, said Soug. The company needs time to explore these, he said, promising an update later in the year.

For now, Targovax will be concentrating its efforts on its Oncos oncolytic adenovirus programs, where the lead product Oncos-102 is in a phase I/II trial in mesothelioma. Given the resources that will be freed up from not going ahead with the TG-01 trial, the company is looking at its options to expand the study.

The large number of ongoing trials combining cancer immunotherapies of one sort or another with standard of care chemotherapy – and the stream of positive data these are generating – raises the question of whether any small biotech can sustain the pace.

Jaderberg told BioWorld it depends on the indication. He was involved in the development of Bristol-Myers Squibb Co.'s Yervoy (ipilimumab) checkpoint inhibitor as a treatment for metastatic melanoma, an indication that has gone from having no specific approved therapies a few years ago, to being "very crowded," he said.

Meanwhile, in mesothelioma, standard-of-care treatment with cisplatin was set in 2003. "For 15 years, nothing was happening," Jaderberg said. Last year two trials combining checkpoint inhibitors with cisplatin were started, but there are no other oncoviruses or other immune activators being tested in mesothelioma, and that provides a rationale to accelerate Targovax's Oncos-102 trial.

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