3 breakthrough data readings from ASCO

“Surprising.” “Paradigm shift.” “First time in history.” You don’t hear that kind of talk very often in cancer care.

Indeed, oncologists are conditioned to view most new therapies with a high degree of skepticism. After all, the vast majority of treatments typically increase lifespan by just a few months, and often with a reduction in quality of life.

So here is a trio of data readings that impressed even this skeptical group. All were unveiled at this year’s American Society of Clinical Oncology (ASCO) meeting. And in any case, the data could have implications for practice.

Phase 3 study Destiny-Breast04 of AstraZeneca and Daiichi Sankyo on Enhertu: In the Phase 3 Destiny-Breast04 study, Enhertu was shown to reduce the risk of disease progression or death by 49% compared to chemotherapy in patients with low metastatic breast cancer. previously treated HER2. The results also showed a 36% reduction in the risk of death compared to chemotherapy.

Most of the trial subjects had hormone-responsive tumors and whose cancer had metastasized and had undergone at least one cycle of chemotherapy. The interim analysis showed that Enhertu prolonged their median overall survival by an additional 6.4 months (and, in the few hormone-unresponsive tumors, by 6.3 months).

The data, revealed in a plenary presentation and published in the New England Journal of Medicine, drew an extended standing ovation from an enthralled crowd of ASCO attendees.

Enhertu, approved as a third-line treatment for patients with HER2-positive breast cancer, generated sales of $214 million in 2021. The new data opens up a multi-billion dollar patient population: people with so-called HER2-low breast cancer, or patients who express little or no HER2. This area had few treatment options.

“Enhertu appears likely to remake the breast cancer landscape,” wrote Tim Anderson of Wolfe Research in a note to investors. “The last time this happened was in 1998 with Herceptin,” which carved out a segment in traditional HER2-positive breast cancer.

Anderson predicts that an additional 50,000 patients in the US, EU and Japan will become eligible, a two- to three-fold increase in the current opportunity for breast metastases.

Enhertu consists of an antibody and a kind of chemotherapy warhead whose payload, when delivered to the tumor, kills adjacent cancer cells. The safety in the trial was consistent with the known drug profile.

DESTINYBreast04’s results, described by SVB’s Andrew Berens as “paradigm shifting,” boosted Enhertu’s consensus earnings. Wall Street forecasts $5.3 billion in global sales of Enhertu in 2026, while Anderson said he expects sales to reach $4.1 billion by 2026 and 5.6 billion by 2032.

Given the large potential impact on breast cancer treatment regimens, “these numbers all seem too low,” Anderson noted.

“We see the standing ovation at the meeting as a testament to the anticipated commercial reception of the drug in this context,” Berens added.

KRYSTAL-1 and KRYSTAL-7 studies from Mirati Therapeutics on adagrasib + Keytruda from Merck: Just two weeks ago, Mirati ran into trouble after presenting data on its experimental drug adagrasib, which is being developed to treat lung cancer linked to the G12C mutation in the KRAS gene. Its stock plummeted when a pre-ASCO summary showed its KRAS inhibitor to be broadly comparable to, if not slightly worse than, a predecessor in a difficult-to-treat subset of lung cancer.

The new data received a warmer reaction. This data, shared by Mirati in an investor presentation at ASCO, comes from the biotech’s KRYSTAL-1 and KRYSTAL-7 trials, providing early evidence that the combination appears tolerable with encouraging efficacy.

Although unconfirmed, the data suggests that this regimen may provide a chemotherapy-free option for previously untreated patients with non-small cell lung cancer, according to Berens.

This was a “surprise,” the analyst noted, adding that the evidence “helps alleviate some investor concerns about the inability to combine a checkpoint inhibitor like Keytruda and any G12C agent due to hepatotoxicity.” .

The absence of a significant increase in liver enzymes was particularly significant. For fear of causing liver damage, oncologists were hesitant to combine Amgen’s first KRAS blocker, Lumakras, with a checkpoint inhibitor, preferring instead to combine it with chemotherapy.

Mirati has the preliminary evidence to warrant further study and, pending confirmation, to take on Lumakras, which is also being tested in combination with Keytruda.

However, Amgen’s upcoming combo data “should be largely disappointing,” Berens said. Thus, Mirati’s unexpected data on KRYSTAL-1 and KRYSTAL-7 “could now be seen as an opportunity for Mirati rather than a class liability”.

Before ASCO, Berens had wondered if adagrasib could even be differentiated from Lumakras. Now poised to kick chemo out of the lung cancer treatment playbook — if this promising evidence comes to fruition — adagrasib has a shot at becoming the eventual winner of KRAS.

GSK’s GARNET Phase 2 study of Jemperli (dostarlimab): While Keytruda made a splash in lung cancer, another immunotherapy made an even bigger splash in advanced rectal cancer. Patients whose tumors had a particular mutation called deficient mismatch repair (dMMR) showed an impressive response to treatment with the PD-1 inhibitor Jemperli.

In the small study of 14 subjects with locally advanced rectal adenocarcinoma, 100% of the 12 patients who completed treatment went into remission. The results were presented at ASCO and simultaneously published in the NEJM.

“I believe this is the first time this has happened in the history of cancer,” said one of the authors of the article.

At a median follow-up of one year, subjects did not require further treatment. It was quite a turnaround, given that all were faced with the prospect of traditional chemo, radiation and probably surgery.

This series of grueling treatments has a solid survival rate (typically 77% at three years), but it could have left them with bowel, urinary and/or sexual dysfunction and possibly the need for colostomy bags. All 12 have also had no clinically significant complications, while about 20% typically have adverse reactions to checkpoint inhibitors.

In an accompanying NEJM op-ed, another cancer researcher called the results “small but compelling” and “cause for great optimism.” However, researchers do not yet know how long it will take to know if a full response to immunotherapy would be curative.

Jemperli, the seventh PD-1 drug to hit the market, has the same mechanism of action as Keytruda, which already has a tumor-agnostic indication in a similar mismatch repair patient population. If these drugs prove curative for rectal cancer, “a breakthrough treatment change” could be in sight: “Eligible patients may no longer have to accept functional compromises to be cured.”

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