“Surprising.” “Paradigm-shifting.” “First time in history.” One doesn’t hear that kind of talk very often in the field of cancer care. 

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

Here, then, are a trio of data readouts that impressed even this skeptical bunch. All were unveiled during this year’s American Society of Clinical Oncology (ASCO) meeting. And in all cases, the data could have practice-changing implications. 

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

Most subjects in the trial had tumors that were hormone-sensitive and whose cancer had metastasized and had been through at least one round of chemo. The interim analysis showed Enhertu prolonged their median overall survival by an additional 6.4 months (and, in the few with hormone-insensitive tumors, by 6.3 months).

That data, revealed in a plenary presentation and published in the New England Journal of Medicine, prompted a prolonged standing ovation from a smitten crowd of ASCO attendees.

Enhertu, approved as a third-line treatment for breast cancer patients with HER2-positive disease, generated 2021 sales of $214 million. The new data open up a multibillion-dollar patient population: individuals with so-called HER2-low breast cancer, or patients who express little or no HER2. That area has had few treatment options.

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

Anderson foresees an additional 50,000 patients across the U.S., EU and Japan becoming eligible, a two- to threefold expansion of the current metastatic breast opportunity. 

Enhertu consists of an antibody along with a kind of chemotherapeutic warhead whose payload, once delivered to the tumor, kills adjacent cancer cells. Safety in the trial was consistent with the drug’s known profile.

The DESTINYBreast04 results, described by SVB’s Andrew Berens as “paradigm-shifting,” ratcheted up Enhertu’s consensus revenues. Wall Street forecast $5.3 billion in worldwide 2026 Enhertu sales, while Anderson said he expects sales to reach $4.1 billion by 2026 and $5.6 billion by 2032.

Given the wide potential impact to treatment regimens in breast cancer, though, “These figures all seem too low,” Anderson noted.

“We see the standing ovation at the meeting as testimony to the anticipated reception of the drug commercially in this setting,” added Berens.

Mirati Therapeutics’ KRYSTAL-1 and KRYSTAL-7 studies of adagrasib + Merck’s Keytruda: It was a mere two weeks ago that Mirati ran into trouble after toplining data on its experimental drug adagrasib, which is being developed to treat lung cancer tied to the G12C mutation in the KRAS gene. Its stock took a tumble when a pre-ASCO abstract showed that its KRAS inhibitor is largely on par, if not slightly worse, than a predecessor in one hard-to-treat subset of lung cancer. 

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

While unconfirmed, the data suggest this regimen may offer a chemo-free option for previously untreated patients in the non-small cell lung cancer setting, 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 because of hepatotoxicity.”

The lack of a significant rise in liver enzymes was particularly meaningful. Out of fear of causing liver damage, oncologists have been hesitant to pair Amgen’s first-in-class KRAS blocker Lumakras with a checkpoint inhibitor, preferring instead to join it with chemotherapy.

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

Amgen’s forthcoming combo data, though, “are largely expected to be disappointing,” Berens pointed out. So Mirati’s unexpected KRYSTAL-1 and KRYSTAL-7 data “could now be seen as an opportunity for Mirati rather than a class liability.”

Prior to ASCO, Berens had questioned whether adagrasib could even differentiate itself from Lumakras. Now poised to shed chemo from the lung cancer treatment playbook – if this promising evidence pans out – adagrasib has a shot at becoming the eventual KRAS winner.

GSK’s GARNET phase 2 study of Jemperli (dostarlimab): While Keytruda made a splash in lung cancer, another immunotherapy made an even bigger one 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 featured at ASCO and simultaneously published in NEJM

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

At a median follow-up at one year, subjects required no further treatment. That was quite a turnabout, considering all were facing the prospect of traditional chemo, radiation and likely surgery. 

This grueling round of treatment does have 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. Nor did the 12 present with any clinically significant complications, whereas about 20% usually have adverse reactions to checkpoint inhibitors.

In an accompanying NEJM editorial, another cancer researcher characterized the results as “small but compelling” and “cause for great optimism.” However, researchers don’t yet know the duration of time necessary to find out whether complete response to immunotherapy would be curative.

Jemperli, the seventh PD-1 drug to come on the market, has the same mechanism of action as Keytruda, which already has a tumor agnostic indication in a similar population of mismatch repair patients. If these drugs do prove to be curative for rectal cancer, “a revolutionary treatment shift” could be in the offing: “Eligible patients may no longer have to accept functional compromise in order to be cured.”