ASCO recap: Breast cancer breakthrough, Mirati’s moves, Arcellx ascends & more

 

The annual meeting of the American Society of Clinical Oncology brought an estimated 50,000 people to Chicago’s McCormick Place aiming for insights into the latest developments in cancer treatments.

The big pharmaceutical companies always make big news at ASCO, and this year was no exception as Gilead Sciences and AstraZeneca each posted data updates that could have strong implications for their respective breast cancer drugs. But some clinical-stage biotech companies also made headlines, unveiling new data suggesting their experimental therapies could offer patients new treatment options. The growth of cell therapy research was reflected in the presentations this year. In addition to the approved CAR T treatments, several companies presented data for their off-the-shelf alternatives. Here’s a recap of some news highlights from the conference.

Breaking breast cancer news

Two years ago, Gilead Sciences plunked down $21 billion to acquire Immunomedics betting that its then recently approved breast cancer drug, Trodelvy, could become a blockbuster. The initial approval for the antibody drug conjugate covers the rare but aggressive triple negative breast cancer. At ASCO, Gilead reported data from a Phase 3 test in HR positive and HER2 negative breast cancer, a more common type of the disease. While the primary analysis shows the study met the main goal measuring progression-free survival, the improvement over chemotherapy was a median six weeks. Overall survival data are not yet mature.

Véronique Dieras, an oncologist at Centre Eugene Marquis in Rennes, France, acknowledged that the Gilead drug met the main study goal. But she added that it’s not yet clear whether that is enough to translate to a better quality of life for patients. “Perhaps my potential concern, when we look to the result of a Phase 3 study, we have to ask about magnitude of benefit and if it’s clinically meaningful,” she said.

Meanwhile, partners AstraZeneca and Daiichi Sankyo posted data that could significantly expand the use of their antibody drug conjugate, Enhertu. The product’s approval currently covers HER2 positive breast cancers. Patients with low HER2 levels have been classified as HER2 negative, based on the thinking that a drug that targets this HER2 genetic signature would not work on patients with low levels of the protein. Data reported for the drug at ASCO suggest otherwise.

The Phase 3 study enrolling “HER2-low” patients; the main goal was to assess progression-free survival. On this measure, the Enhertu group lived a median 10.1 months compared to a median 5.4 months for those who received chemotherapy. Jane Meisel, a professor of hematology and oncology at Emory University and an ASCO breast cancer expert, described the results as “practice changing.”

Enhertu does come with some lung toxicity risks. Memorial Sloan Kettering Cancer Center’s Shanu Modi, the lead investigator for the study, acknowledged these risks but said clinicians can monitor for these adverse effects and manage them when they arise.

Progress for BCMA-targeting drugs

Partners Johnson & Johnson and Legend Biotech won FDA approval last year for Carvykti, a CAR T cell therapy that treats multiple myeloma by targeting a protein called B-cell maturation antigen (BCMA). That decision was based on Phase 1b/2 data. Legend now has longer term data showing the durability of the therapy after more than two years and those results were presented at ASCO.

In heavily pretreated multiple myeloma patients whose disease relapsed or had not responded to earlier treatment, Legend reported a 98% overall response rate at a median 28-months of follow up. At the time of the follow up, data were not available for median progression-free survival or median overall survival, which the company said suggests the long-term durability of responses and survival of patients treated with the drug.

In addition, a separate study is underway evaluating Carvykti as an earlier line of treatment in 20 multiple myeloma patients who had previously received one to two lines of prior therapy and whose disease cannot be treated with Revlimid, a standard of care drug for myeloma. At a median follow-up of 17.1 months, Legend reported a 95% overall response rate; 90% of patients achieved a complete response or better.

Arcellx is a relative latecomer to targeting BCMA for treating multiple myeloma, trailing Carvykti and Bristol Myers Squibb drug Abecma, which was approved last year. But Arcellx brings different technology to the BCMA hunt—synthetic binding domains it calls D-Domains—and it presented early Phase 1 data at ASCO suggesting its approach could offer even better efficacy.

A total of 31 patients from the Phase 1 expansion study were evaluable for efficacy and safety at least one month following treatment. As of a May 3 cutoff date, Arcellx reported its therapy, CART-ddBCMA, achieved a 100% overall response rate. The complete response rate was 71% (22 of 31 patients). Toxicities have been manageable and all of them resolved with standard treatment at both of the dose levels tests. Arcellx said that there were no cases of neurotoxicity or parkinsonian symptoms.

In a research note, William Blair analysts Raju Prasad and Sami Corwin wrote that the strong clinical activity and durability of Arcellx’s therapy has de-risked the company’s technology. If the pivotal study recruits patients with prognoses better representative of population of relapsed and refractory multiple myeloma patients—similar to those enrolled in Legend’s study—William Blair believes a successful clinical trial could make the Arcellx therapy best in the class of BCMA CAR T therapies.

Adicet nails down key data for off-the-shelf CAR T

Off-the-shelf cell therapies are seen as key for making these treatments more widely available in part because the process of making personalized cell therapies from a patient’s own T cells is lengthy and expensive. Adicet Bio continued to post data supporting its approach, which uses a rarer type of T cell, called gamma delta T cells, which are sourced from healthy donors. Last year, the biotech reported preliminary Phase 1 data from four patients indicating that its approach is working. At ASCO, Adicet provided an update on the study, enrolling patients with advanced B-cell non-Hodgkin’s lymphoma.

As of a May 31 data cutoff, Adicet now has data from eight total patients. In this group of heavily pre-treated patients who had received a median of four prior treatments, the Adicet therapy ADI-001, led to a 75% overall response rate and a complete response at all dose levels. In three patients that relapsed after previously receiving an autologous CAR T-therapy, Adicet reported that all of them responded to ADI-001. In addition to the manufacturing edge of an off-the-shelf therapy, Adicet aims to offer safety advantages as well. The company reported no dose-limiting toxicities, nor were there any immune responses or neurological problems that are associated with CAR T treatments. Adicet said it expects to identify a recommended Phase 2 dose in the second half of this year; at least one study that could support a registrational filing could start in the first half of 2023.

Bringing mRNA to cancer vaccines

Before BioNTech became known for its Covid-19 vaccine, it was applying its messenger RNA technology to the development of cancer vaccines. At ASCO, the German company reported preliminary data from a Phase 1 study evaluating autogene cevumeran, a personalized mRNA-based vaccine based on neoantigens from the patient. This vaccine is being developed as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) that has been surgically removed. The program is progressing under a partnership with Roche; BioNTech’s cancer vaccine candidate is being tested in combination with Roche immunotherapy atezolizumab and chemotherapy.

BioNTech reported preliminary results showing that of 16 patients who received the combination, the treatment was well tolerated. A neoantigen-specific T cell response was observed in 50% of patients (eight of 16). At a median follow-up of 18 months, eight patients with de-novo immune responses had a significantly longer recurrence-free survival compared with those that did not have vaccine-induced immune responses. Based on these early results, the partners are now planning a randomized study to further evaluate the treatment combination patients with resected PDAC.

Mirati moves in on Amgen’s KRAS drug

KRAS mutations were long thought to be undruggable. That changed last year with FDA approval for Lumakras, an Amgen drug that treats non-small cell lung cancer by targeting the rare KRAS G12C mutation . Mirati Therapeutics aims to offer an alternative with its drug, adagrasib, and the company revealed at ASCO more data from the therapeutic candidate’s pivotal study.

On efficacy, the Mirati drug appears comparable to the Amgen product. But Mirati aims to differentiate its drug on its ability to treat NSCLC that has metastasized to the central nervous system. Of 19 evaluable patients, the objective response rate was 32%. Three patients achieved a complete response and three others achieved a partial response. In a research note, William Blair analyst Matt Phipps acknowledged adagrasib’s CNS activity but he added that it’s unclear whether that’s enough to differentiate the drug given its similar efficacy data in the general population. Adagrasib is currently under FDA review; a decision is expected by mid-December.

Speaking of undruggable targets…

The p53 protein has been regarded as something of a holy grail for drug hunters. It has several anti-cancer properties but has been an elusive drug target. PMV Pharmaceuticals reported at ASCO its first clinical data indicating that its small molecule can drug p53, with results spanning a range of tumor types, including ovarian, prostate, and pancreatic cancers. In the dose-escalation part of the Phase 1/2 study, PMV reported a 32% overall response rate (eight of 25 patients).

Dose-limiting toxicity was reported in two patients at the highest dose, but the company said it is working to identify a lower dose that balances safety and efficacy. The clinical trial is continuing to determine the dose to advance to Phase 2 testing that the company expects could begin early next year. Meanwhile, PMV also plans to move forward with a Phase 1 study testing its drug in combination with a checkpoint inhibitor.

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