AstraZeneca's bispecific antibody candidates create “an incredible richness” for the company's cancer pipeline, CMO Massacesi said.
AstraZeneca, home of cancer blockbusters like Tagrisso and Daiichi Sankyo-partnered Enhertu, wants to elevate its cancer pipeline and is sharing a peek at data from three bispecific antibody candidates at this year's European Society for Medical Oncology (ESMO) Congress.
The Big Pharma’s “2.0 portfolio,” as Chief Medical Officer and Oncology Chief Development Officer Cristian Massacesi, M.D., calls it, centers largely around bispecific antibodies, engineered drugs that can bind to two different tumor antigens. Using a second mechanism in combination with the rest of the portfolio could be truly transformative, Massacesi told Fierce Biotech.
As a class, bispecifics offer several benefits. The most obvious benefit is convenience—receiving one drug is fundamentally easier than two, Massacesi explained.
Beyond that, bispecifics are known to improve both efficacy and safety because of their ability to bind two different antigens. The targeted therapeutic also holds the potential to overcome challenges that can pop up when drugs are co-administered, like drug-drug interactions.
AstraZeneca believes it has a unique approach, in part due to its proprietary bispecific platform, which has allowed the pharma to introduce fewer mutations that are needed to create the correct pairing, Puja Sapra, Ph.D., AstraZeneca’s head of R&D biologics engineering and oncology targeted delivery, told Fierce. The limited mutations help maintain structural integrity and could potentially boost immunogenicity and certain desired pharmacokinetic properties.
“Our strategy in oncology is developing multiple platforms that can tackle the cancer cell at different levels,” said Massacesi. Current cancer treatments that work well—such as chemotherapy and radiotherapy—aren’t selective enough, something that has prompted AstraZeneca to fill out its portfolio with antibody-drug conjugates (ADCs) because they're highly selective.
ADCs, which merge antibodies and chemotherapy together, have been all the buzz at this year’s ESMO. AstraZeneca is no stranger to the space, having partnered with ADC expert Daiichi Sankyo on Enhertu and more. The two plan to file for approval of ADC datopotamab deruxtecan (Dato-DXd) after linking the treatment to improved outcomes in breast cancer in a recent phase 3.
AstraZeneca has a large portfolio of its own ADCs, some of which will be improved upon by using the bispecific platform, Massacesi said. Combining different modalities, such as a bispecific with an ADC, is the only way to really kill cancer cells, according to Massacesi.
“This is exactly our strength as a company,” the CMO said. “Where we believe that we will be upfront—very competitive—is putting together the next mechanism set and bringing the treatment benefit to the next level.”
Bispecifics can still be considered a newer science, with Amgen’s Blincyto the first to snag FDA approval in 2014 for Philadelphia chromosome-negative B-cell acute lymphocytic leukemia. Most recently, Roche’s Columvi received an FDA nod for relapsed or refractory diffuse large B-cell lymphoma or large B-cell lymphoma in June, less than a month after AbbVie and Genmab won approval for bispecific Epkinly.
While AstraZeneca doesn’t have any approved bispecific therapies, one of the Big Pharma’s candidates, volrustomig, is moving its way closer to the FDA finish line. The bispecific antibody targets CTLA-4 and PD-L1, and is currently being assessed in several clinical trials. Two of those studies are phase 3 studies—one as a monotherapy in advanced cervical cancer and another as a combo with chemotherapy for patients with metastatic non-small cell lung cancer (NSCLC). The company also plans to launch additional phase 3 studies, according to Massacesi, noting that AstraZeneca believes the asset should be ready for registrational programs soon.
After making its ESMO debut with early phase 1/2 NSCLC data last year, volrustomig is back again, this time in renal cell carcinoma. The new data looks at a phase 2 expansion cohort of 65 patients who received the bispecific as a first-line treatment.
Researchers learned from earlier data that dose-limiting toxicities arose at the 1,500 mg dosage and therefore only administered 500 mg and 750 mg doses to mitigate risk. The toxicities are very much related to the dosing level, Massacesi explained, adding that 750 mg was better tolerated, even when given in combo with chemotherapy.
New data demonstrated an objective response rate (ORR) of 45.5% and 48.4% for the low and high-dose cohorts, respectively, but only five complete responses (CRs) between the two dosing groups. Median duration of response was 17 months for patients receiving 750 mg, while patients in the 500 mg group had a response duration of 11.5 months. Nearly half (28) of patients discontinued treatment because of a treatment-related adverse event.
“This is a phase 2, so it’s still very preliminary,” said Massacesi, adding that some patients maintained a good response even after the drug is discontinued.
Despite the discontinuation rate, Massacesi claimed that the data remains compelling, citing the durability and response rate and adding that CRs sometimes increase as time goes on. The patients require a follow-up to track that, Massacesi said.
The investigational treatment compares well to the standard-of-care in renal cancer, especially given the poor prognosis for the population generally, according to Massacesi. An estimated 81,800 new cases and 14,890 deaths from kidney and renal pelvis cancer occur in the U.S. each year, based on 2020 data from the National Cancer Institute.
Right now, a main player in the market is Bristol Myers Squibb’s Opdivo, a PD-1/PD-L1 inhibitor that's often combined with another of its drugs, Yergovy, which targets CTLA-4, though the pair failed a phase 3 trial last year as an adjuvant treatment for patients with localized renal cell carcinoma.
AstraZeneca also shared new data on another investigational bispecific, sabestomig, in patients with PD(L)1- resistant non-small cell lung cancer (NSCLC). The bispecific is designed to target PD-1 and TIM-3, and the new phase 1/2a data revealed zero patient discontinuations. While almost every patient (43/45) reported an adverse event, only two of these were deemed related to treatment.
“The safety is very, very similar to what you expect back with the PD-1 or PDL-1 alone,” Massacesi explained. That feature makes sabestomig, in theory, very combinable with chemotherapy, ADCs or other modalities, something that makes sabestomig “instrumental” to AstraZeneca’s development strategy.
Third up is rilvegostomig, a bispecific antibody targeting PD-1 and TIGIT aimed at patients with advanced and pretreated NSCLC. In preclinical models, the combination of a PD-1 plus TIGIT combo versus rilvegostomig favored the bispecific, Sapra said, with comparable, if not better, results.
The newest data is an early slice from a phase 1/2 trial that zoomed in on safety and found no dose-limiting toxicities during dose escalation. In total, three (3.6%) patients—all of whom were receiving the highest dosage—discontinued treatment due to adverse events. These events were considered treatment-related for two patients, both of whom recovered after taking steroids. Four (4.8%) patients had adverse events leading to death, none of which related to rilvegostomig.
“We are very happy with the safety profile of the drug,” Massacesi said, noting that it’s too early to try to predict efficacy and that the study was designed to confirm dosing levels and safety.
While it’s been a wild rollercoaster of a year for TIGIT-focused drugs—think Novartis’ retreat from the space and Roche’s tiragolumab whiplash—Massacesi said AstraZeneca still views the class as highly important. It’s too soon to say if rilvegostomig can overcome some of the challenges other anti-TIGIT checkpoint inhibitors have faced, namely efficacy, but Massacesi believes TIGITs should be used in settings where a PD-1 would be beneficial and then a TIGIT can improve further.
“PD-1 positivity seems to be the way, but we need to learn more,” he noted. While one TIGIT alone can be beneficial, Massacesi said something more is probably needed—which is how he believes AstraZeneca will win in the space.
“We are going to be very competitive, combining this PD-1 TIGIT with the rest of our portfolio,” the CMO said.
Volrustomig, sabestomig and rilvegostomig create “an incredible richness” for AstraZeneca’s portfolio because the company can position the three different drugs not only across different tumor types but also in the same tumor type using different combinations, Massacesi explained.
From a technology perspective, the bispecific antibodies are “just the foundation,” according to Sapra, who said the company can now make a bispecific ADC, for example.
“We are applying this technology outside oncology for other therapeutic areas as well,” Sapra added. “So all the knowledge that has been accumulated and built in the technology is helping us with the entire portfolio.”
Editor's note: This article was updated at 2 p.m. ET on Oct. 24 to clarify where volrustomig stands in the registrational process.
