5 takeaways from AACR, one of the year's top meetings on cancer drugs
The American Association of Cancer Research's virtual meeting, one of the year's biggest conferences in oncology, was in full swing over the weekend and will continue over the next few days. Though the gathering typically focuses on early research and clinical work — rather than the larger trials that change medical practice — there has been a bit of both at this year's meeting.
Key updates included fresh data on a new immunotherapy target, encouraging results for a new type of cell therapy and a closer look at what Sanofi bought in its 2019 buyout of Synthorx. Also reported were a glimpse at Eli Lilly's second effort in KRAS and Bristol Myers Squibb's push into early cancer with Opdivo.
An emerging target for cancer immunotherapy
Cancer immunotherapies known as checkpoint inhibitors have changed the way a wide range of cancers are treated.
But a sizable share of patients still don't benefit from treatment, which is why drugmakers have spent years trying to pair immunotherapies and other types of drugs, with mixed results. The most successful regimens so far have combined immunotherapies and old-fashioned chemotherapy.
But new approaches keep emerging. One fast gaining traction involves a class of drugs that block a protein called TIGIT.
Like checkpoint inhibitors, TIGIT-targeting drugs block a protein tumors use to evade the immune system. But they spur an immune response as well, which could help boost effectiveness of other drugs. TIGIT blockers from Roche and Merck have each shown potential when paired with checkpoint inhibitors. At AACR, a biotech called iTeos Therapeutics joined in with an early look at a drug called EOS-448.
The results are from an early stage study testing the treatment by itself. One patient, whose melanoma resisted Keytruda, partially responded to treatment. Nine others with advanced solid tumors had stable disease. The most severe side effects were rash and a systemic inflammatory response.
Given investor expectations were high, some "will be disappointed," wrote SVB Leerink analyst Daina Graybosch. But the results nonetheless "look similar" to what's been reported for other TIGIT blockers, she said.iTeos shares fell by more than 6% on Monday.
Early promise for a new kind of cell therapy
Over the last decade, cell therapy has become a viable treatment option for patients with some types of advanced blood cancers like leukemia and lymphoma. But the reach of so-called CAR-T treatment remains limited, and researchers have begun to test other types of cells as they seek to improve on the first generation of therapies.
A leading approach involves genetically altering natural killer cells — part of the body's first line of defense against foreign invaders — instead of the T cells harnessed in CAR-T treatment. The concept, being developed within biotechs like Fate Therapeutics, Nkarta Therapeutics and others, has drawn interest from several large drugmakers.
Early data trickling out of a program developed at the MD Anderson Cancer Center has shown why, as an NK cell-based treatment produced encouraging responses in non-Hodgkin lymphoma patients, but without the severe side effects commonly associated with CAR-T. The treatment uses cells from cord blood, meaning it could potentially be given on demand, or "off the shelf."
More promising news was on display at AACR. Four lymphoma patients received a similar NK cell treatment — along with an experimental antibody drug from Affimed meant to boost its effects — in an early-stage trial. Those patients' disease had progressed despite at least four, and as many as 14, different drugs. All four patients responded to treatment, including two who went into remission.
It's unclear how long those responses will last, but the results "support proof of concept [and] potential for an elegant ... off-the-shelf NK cell approach," wrote Jefferies analyst Maury Raycroft.
Sanofi, Synthorx and the push to fix IL-2
Drugmakers have been intrigued for years by the cancer-fighting potential of IL-2, an inflammatory protein with the potential to dial an immune response up or down but can be highly toxic. Many patients who get the available treatment, Proleukin, develop a side effect called vascular leak syndrome in which their blood vessels leak fluid, causing swelling and other issues.
A new wave of IL-2 drugs either engineered or tweaked in other ways are aimed at overcoming those limitations, however, and they've drawn the interest of pharmaceutical companies as potential partner therapies.
Drugs from Nektar Therapeutics and Alkermes, for instance, are in or approaching late-stage tests with drugs like Opdivo and Keytruda. Since 2019, Merck and Sanofi have each spent billions of dollars on biotechs — Pandion Therapeutics and Synthorx, respectively — with IL-2 treatments in development. The first clinical data underlying Synthorx's program, THOR-707, were disclosed at AACR.
But the results leave some doubts. Three of 45 patients with advanced, metastatic solid tumors partially responded to treatment in testing. None had a complete response, while two also received Keytruda, making the benefit THOR-707 harder to distinguis
Still, there were no instances of vascular leak syndrome, Sanofi is still testing higher doses, and Stifel analyst Benjamin Burnett noted there appears to be an "early trend of deepening responses to treatment," something that has been seen in testing of Nektar's drug. THOR-707 "looks active in a manner that's consistent with other IL-2 [drugs]," he wrote.
Lilly re-emerges as a KRAS competitor
Last year, Eli Lilly was one of several companies following quickly on the heels of Amgen in developing a drug aimed at cancers harboring mutations in a gene called KRAS.
After decades of nothing working, breakthroughs in biology and chemistry had shown a way to target KRAS, one of the most commonly altered genes linked to tumors. Amgen was first, with a drug now known as sotorasib advancing quickly through early clinical studies. Lilly, Mirati Therapeutics, Boehringer Ingelheim, Johnson & Johnson and others sought to do the same with competing therapies.
But Lilly's first attempt ended quietly in July, when the pharma company noted in a presentation that its KRAS-blocking candidate had been discontinued due to unexpected toxicity in a Phase 1 trial.
Nine months later, Lilly's back with a presentation at AACR detailing its second effort, a molecule known as LY3537982. Preclinical testing suggests the experimental compound could be more potent than both Amgen's sotorasib and another drug from Mirati.
According to David Hyman, chief medical officer of Lilly's cancer division, Lilly has gone "above and beyond" in addressing the toxicity concerns that led it to end work on the first molecule.
"If the only thing that was different between this effort and the last was solving this off-target toxicity, we wouldn't have advanced the program," he said in an interview. "What really caused us to decide to advance this program was the total data package, best exemplified by the potency gains we've seen in this compound vis-a-vis the last program and looking across the space."
Still, he added, preclinical models can't show whether gains in potency will translate into a more effective, or safer drug. The first attempt at answering that question with come sometime later this year, when Lilly starts a Phase 1 study.
Another step in immunotherapy's march to early-stage cancer
Cancer immunotherapy is already well-established in advanced disease, where drugs like Keytruda, Opdivo and Tecentriq are approved to treat tumors of the lung, skin, and other organs that have already begun to spread.
But drugmakers are now deep into trials testing immunotherapies earlier in a patient's disease course, either before or after surgery to remove a tumor. Keytruda and Opdivo are cleared in early skin cancer, for instance, and Bristol Myers Squibb, Merck & Co. and others are working to gain similar approvals for other tumor types.
At AACR, Bristol Myers gave its latest pitch for Opdivo in early disease, detailing Phase 3 results in patients with non-small cell lung cancer who were treated before surgery. The results show 24% of patients who received Opdivo and chemotherapy had a pathological complete response — no trace of cancer on tissue removed during surgery — compared to 2.2% of those who got chemotherapy alone.
The Food and Drug Administration may want to see more, however. The agency just rejected an application from Merck to use Keytruda in a form of breast cancer both before and after surgery, asking for more data. Merck doesn't yet know whether the regimen can keep cancers at bay longer than standard care, and that's a question Bristol Myers doesn't have an answer to yet either.
Johns Hopkins study investigator and lung cancer specialist Patrick Forde noted several studies have suggested an "association" between pathological complete responses and survival in non-small cell lung cancer. Historically, there is a median 4% rate of such responses with chemotherapy alone, something the addition of Opdivo seems to have improved upon.
"Personally I'm hopeful. The difference is significant,” Forde said on a call with reporters. But "that's the key question we'll address next as the data mature further."
AUTHOR Ben Fidler@BentheFidler, Ned Pagliarulo@NedPagliarulo
PUBLISHED BioPharma Dive April 12, 2021 https://www.biopharmadive.com/news/aacr-2021-takeaways-immunotherapy-tigit-kras-il2/598189/