ASCO: Has AstraZeneca finally found a place for long-plagued I-O candidate tremelimumab?

AstraZeneca
AstraZeneca is still waiting for its first FDA approval for a tremelimumab-containing regimen. (AstraZeneca)

AstraZeneca’s CTLA4 candidate tremelimumab has suffered a host of clinical failures that have so far kept it off the market. But new phase 2 results show the company might just be able to use the drug in a new way.

Starting previously treated liver cancer patients on a single, 300-mg initial dose of tremelimumab and following up with PD-L1 therapy Imfinzi helped patients live a median 18.7 months in a phase 2 study, AstraZeneca said ahead of the American Society of Clinical Onocolgy (ASCO) virtual annual meeting this weekend.

That figure was well above the 13.6 months Imfinzi posted on its own or the 15.1 months solo tremelimumab produced. Another Imfinzi-tremelimumab combo with a lower, 75-mg dose of tremelimumab performed worst of all in terms of extending lives, doing so by a median 11.3 months.

The regimen with the higher tremelimumab dose, dubbed T300+D for short, also led the others in terms of response rate. It spurred a benefit in 24% of patients versus 10.6% for Imfinzi monotherapy, 7.2% for tremelimumab monotherapy and 9.5% for the second combo.

AstraZeneca’s investors aren’t exactly used to seeing tremelimumab improve a regimen’s performance. The combo of the candidate plus Imfinzi famously flopped AstraZeneca’s phase 3 Mystic trial back in 2017, keeping the duo out of the lucrative market for previously untreated metastatic non-small cell lung cancer (NSCLC).

RELATED: AstraZeneca's tremelimumab records another miss as Imfinzi combo strikes out in small cell lung cancer

But tremelimumab has faltered in other indications, too, including bladder cancer and, most recently, small cell lung cancer. And those missteps have puzzled industry watchers, especially as Bristol Myers Squibb’s CTLA4 drug, Yervoy, continues to rack up FDA green lights across multiple cancers in tandem with PD-1 drug Opdivo.

Using tremelimumab as a primer, though, is “a different approach to the administration of tremelimumab than we’ve taken in some other studies,” said Dave Fredrickson, executive vice president and global head of AstraZeneca’s oncology business unit. And while the study is on the small side, “we’re seeing really good indications of efficacy,” he noted.

The performance may bode well for AstraZeneca’s phase 3 Himalaya study, set to read out in the second half of this year, where the British drugmaker is hoping its duo can replicate its success, this time in previously untreated patients—a group that has over the years proved difficult to treat.

That trial, too, “utilizes that single high dose” of tremelimumab followed by Imfinzi, making the latest data “potentially a meaningful indicator into what we hope we might see in the larger phase 3,” Fredrickson said.

If Himalaya proves successful, AZ could get a shot at a market that only just got its first immuno-oncology player this Friday with the FDA approval of Roche’s Tecentriq-Avastin pairing. But Merck’s Keytruda-Lenvima combo—already bearing a breakthrough therapy designation—is chasing a nod of its own, and it bolstered its case with overall response data at ASCO over the weekend.

RELATED: ASCO: Bristol's Opdivo-Yervoy-chemo trio cuts lung cancer death risk by up to 38%

Meanwhile, AstraZeneca isn’t alone in exploring ways to sequence its checkpoint meds for maximum efficacy. Another closely watched ASCO data set showed that adding two early cycles of platinum chemo to Opdivo and Yervoy in first-line NSCLC could dramatically up response rates compared with Opdivo-Yervoy alone, resulting in an FDA go-ahead for the chemo-containing cocktail earlier this week.

When it comes to immuno-oncology, “we know that not all patients are responding, and even among those who respond, some have inadequate responses,” Fredrickson said. And while getting the right combination of drugs and using drugs in the right patient subtypes are both critically important, getting the right dose, administration and sequencing of those drugs are important, too.

“I think you see work happening in all of these dimensions,” he said.

Vanessa Lucey, Ph.D., director of the Cancer Research Institute Venture Fund and Clinical Accelerator, agrees. “Looking at the landscape across all the clinical trials, a lot of these combinations, especially with chemotherapy, are doing those different iterations,” she said during last week’s FiercePharma ASCO preview webinar. “Hopefully there will be some data sets in the future that can lend (themselves) to maybe expanding out what BMS has demonstrated … but in different tumor types.”

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