ASCO preview: How Gilead, Pfizer, AstraZeneca-Daiichi breast cancer data may—or may not—change treatment practice

Three sets of trial data to be presented at the annual American Society of Clinical Oncology (ASCO) meeting this weekend could shake up breast cancer treatment—and are therefore closely followed by industry watchers. They belong to Gilead Sciences’ Trodelvy, Pfizer’s Ibrance and AstraZeneca and Daiichi Sankyo’s Enhertu.

For a preview of those studies, Fierce Pharma talked to Debu Tripathy, M.D., chair of breast medical oncology at the University of Texas MD Anderson Cancer Center. Here, he walks us through why the new data may—or may not—be important to specific breast cancer types and those drug developers.

All three drugs are either already blockbusters or promise to break the blockbuster barrier in the future. The new data might determine whether a drug stays a leader in its class or offer an important signal of a newcomer’s growth potential. No matter what the data prove to be, “the fact that we’re talking about these three important trials in one meeting is a testimony as to how quick the progress is going now,” Tripathy said.

 

Can Trodelvy reach a wider patient group?

 

Background: Gilead bought Trodelvy in its $21 billion acquisition of Immunomedics in 2020, and CEO Dan O’Day quickly labeled the TROP2-targeted antibody-drug conjugate as a cornerstone of the Big Biotech’s newfound oncology focus.

Wall Street analysts calculated that for Gilead to get a return on the investment, Trodelvy needs to reach $4 billion in peak sales. The drug’s current use for triple-negative breast cancer (TNBC) after two prior therapies won’t be enough to get there. Gilead's aiming to move Trodelvy up the TNBC treatment line, but it's also eyeing a bigger patient pool in HR-positive, HER2-negative breast cancer—an opportunity that could be worth $2 billion, analysts have said.

Enter the phase 3 TROPiCS-02 trial, which pits Trodelvy against chemotherapy in heavily pretreated HR+/HER2 patients. In March, Gilead said the trial hit its primary endpoint, showing Trodelvy was better than chemo at staving off disease progression or death.

But in a twist, Gilead hinted that the improvement, though statistically significant, might not be clinically meaningful in some people’s view. The lack of a clear win sent Gilead’s stock south. Now, the detailed data at the interim analysis will be presented at ASCO 2022.

Expert input: Tripathy said “the minimum improvement” that he—and most doctors—would like to see is a 30% reduction in the risk of disease progression or death. Based on his experience that this kind of patient typically lives about six to seven months without disease worsening while on chemo, Tripathy said a progression-free survival (PFS) extension of less than two to three months “would not really be worth it.”

Tripathy’s comment matches the result of a survey RBC Capital Markets did with 36 breast cancer-treating oncologists after Gilead’s revelation in March. In the survey, 92% of doctors said they wanted to see a PFS advantage of at least two months. And the three doctors who would accept a lower bar only accounted for 5% of the breast cancer patients seen by the group.

Gilead has said the TROPiCS-02 trial remains ongoing to read out the all-important overall survival data. The company said it had seen a favorable trend in the data suggesting Trodelvy could extend patients’ lives.

Acknowledging that the overall survival data may still be immature at this point, Tripathy said he would like to eventually see Trodelvy prolonging lives by at least two to three months. In RBC’s survey, the average overall survival benefit that the doctors wanted was 2.3 months, and 75% of them said they’d be willing to use Trodelvy if the number hits two months.

But as Tripathy noted, historically, only drugs that indirectly affect tumors through the immune system have succeeded in achieving a wider improvement in patient survival after a modest disease progression effect, and Trodelvy doesn’t work that way.

 

Will Ibrance lose the CDK crown?

 

Background: As the first CDK4/6 inhibitor on the market, Pfizer’s Ibrance has maintained a huge market lead over later competitors. In 2021, the HR-positive/HER2-negative breast cancer drug sold $5.44 billion worldwide, up 1% year over year.

But Ibrance has lately come under some pressure in the U.S., especially when it comes to share of new patient starts. While Novartis’ Kisqali and Eli Lilly’s Verzenio are expanding their new-to-brand script numbers, Ibrance’s new patient scripts appear to have plateaued with a faint sign of decline.

So far, Ibrance is the only CDK4/6 drug without a life-extension win in a phase 3 clinical trial. In the phase 3 PALOMA-3 trial, adding Ibrance to AstraZeneca’s hormone therapy Faslodex failed to beat solo Faslodex at extending the lives of previously treated patients with advanced disease. What’s more, the Pfizer drug failed in two trials, PALLAS and PENELOPE-B, that tested it as a postsurgery adjuvant therapy in patients with early-stage disease.

Over the past few years, though, Pfizer has been leveraging its years of head start and doctors’ familiarity with Ibrance as well as real-world evidence.

Finally, at the ASCO 2022 meeting, Pfizer will present overall survival data from the PALOMA-2 trial, which could be Ibrance’s last chance at proving itself in a phase 3 clinical trial. The study compares Ibrance and Novartis’ hormone therapy Femara as a front-line treatment in postmenopausal women. The trial earned Ibrance that indication more than five years ago based on data showing the drug could stall disease progression or death.

Expert input: Doctors do put some weight on real-world data, but they also understand that “the statistical rigor” isn’t as strong as a clinical trial, Tripathy said. “If the clinical trial did not show a survival benefit, people are not as confident that the real-world data reflects the truth.”

Nevertheless, he pointed out that it would also be difficult to draw cross-trial comparisons, because the CDK drugs’ clinical trials enrolled patients with different baseline characteristics. And, because PALOMA-2 was the first of its kind, Ibrance might be at a disadvantage from a trial design perspective, Tripathy suggested.

Thanks to all the complexities, Tripathy sees the PALOMA-2 overall survival data as “more important psychologically than it is clinically.” After all, when doctors have the treatment choice conversation with their patients, the fact that only the two other CDK4/6 inhibitors are associated with a survival benefit will come up.

It’s been a long time since PALOMA-2 reported its win on progression-free surivival. So, even if the trial now shows Ibrance patients lived longer, people will have to wonder how much of that effect was actually Ibrance's doing, Tripathy argued.

If the study misses its overall survival endpoint, Tripathy said Ibrance will further lose its market share “little by little”—rather than “a sudden drop off the cliff”—but it will continue to be the leader of the class. He did note that Ibrance still appears to have the best toxicity profile among the three.

 

Can Enhertu open a new breast cancer venue?

 

Background: Breast cancer patients are currently grouped into three large categories: HER2-positive, HR-positive/HER2-negative and triple-negative. But with Enhertu, Daiichi Sankyo and partner AstraZeneca aim to open a new group: HER2-low.

Traditionally, HER-positive patients are defined by HER2 protein expression on an immunohistochemistry (IHC) assay at a score of 3+ or IHC 2+ accompanied by a positive in situ hybridization (ISH) test. The rest are considered HER2-negative. But AZ and Daiichi are now carving out those with IHC 1+ or IHC 2+ with a negative ISH score—and calling them the HER2-low group.

In February, the two companies said the phase 3 DESTINY-Breast04 trial showed Enhertu topped physician’s choice of chemotherapy in both progression-free and overall survival in patients with previously treated HER2-low breast cancer. Improvement from the HER2-targeted antibody-drug conjugate was statistically significant and clinically meaningful, the pair said. Now, they are presenting detailed data during a plenary session at ASCO 2022.

Up to 55% of breast cancer patients fall into that HER2-low definition. These patients currently aren’t eligible to receive a HER2-targeted agent.

Previously, Roche’s anti-HER2 drug Herceptin, which forms the antibody part of Enhertu, had failed in a HER2-low trial. Called NSABP B-47, the 3,270-participant study found that adding Herceptin to adjuvant chemotherapy after surgery in HER2-low early-stage breast cancer didn’t improve the chance of patients experiencing disease recurrence, diagnosis of a new cancer or death. Because that large trial had failed, the dichotomy of HER2-positive and HER2-negative stayed in place.

Expert Input: The situation could be different with Enhertu. Rather than using Herceptin to block HER2 signaling, Enhertu is using HER2 as a “homing signal” to send the real cancer-killing weapon, which is a toxic chemotherapy payload, Tripathy explained. So, the required threshold for the level of HER2 expression may be lower, he said.

As with Trodelvy, Tripathy wants to see about a reduction of about a third in both PFS and overall survival to call Enhertu worthwhile in this new breast cancer population. He expects more leniency toward the overall survival marker, given that data set may be a little early at this point.

On the flip side, because Enhertu’s mechanism basically involves a supposedly fast-action chemotherapy to neutralize tumor cells, Tripathy suspects the drug should be able to report a definite survival readout sooner than the CDK4/6 drug class has in the past.

Meanwhile, industry watchers will also likely keep a close eye on performance by patient subgroups as divided by their IHC scores. DESTINY-Breast04 isn’t statistically powered to run subgroup analyses for IHC1+ and IHC2+ patients separately, Tripathy noted, and earlier trials didn’t suggest people with even lower HER2 expression benefited any less from Enhertu.

“But if there’s a major discrepancy, that may raise some eyebrows,” Tripathy said. “It may force the FDA to have them do some additional studies to parse out the difference between the two.”