NEW YORK – Three next-generation mutant PI3Kα inhibitors demonstrated promising activity in hormone receptor (HR)-positive, HER2-negative advanced breast cancer and caused minimal high-grade hyperglycemia in studies presented at the San Antionio Breast Cancer Symposium on Tuesday.
The data fulfilled oncologists' expectations for a better tolerability profile for some of these newer, more mutant-selective drugs in this class.
Two of the investigational mutant PI3Kα inhibitors that clinical trial investigators presented results on, Relay Therapeutics' RLY-2608 and Scorpion Therapeutics' STX-478, will go on to further clinical studies. The third, LOXO-783, will not be studied further by sponsor Eli Lilly due to high rates of diarrhea it caused in clinical trial participants. Lilly will now turn its focus to a different preclinical mutant PI3Kα inhibitor it hopes will prove more tolerable.
First look at RLY-2608
At the symposium, Relay presented results from a Phase I first-in-human trial of RLY-2608 and the selective estrogen receptor antagonist fulvestrant in 52 patients with advanced HR-positive, HER2-negative breast cancer harboring mutations in PIK3CA, the gene that encodes PI3Kα. Patients on RLY-2608 and fulvestrant lived a median 9.2 months, and the six-month progression-free survival rate was 66 percent in patients with all types of PIK3CA mutations in their tumors.
For the subset of patients who received RLY-2608 as a second-line treatment, the median progression-free survival was 11.4 months. The rate of all grade hyperglycemia was 46.9 percent at the recommended Phase II dose, but just two patients, or 3.1 percent, had grade 3 hyperglycemia. The overall safety profile was favorable, with minimal adverse events commonly seen with nonmutant-selective inhibitors of the AKT pathway, according to Relay. PI3Kα mutations occur in the AKT pathway.
"The results to date have shown for the first time that the selective mechanism seems to have a substantial benefit in efficacy compared to existing agents, which currently provide [progression-free survival of] about five and a half or six months," Ben Wolf, Relay's chief medical officer, said in an interview. He added that compared to the first-in-human data for Roche's PI3Kα inhibitor Itovebi (inavolisib), "the results we presented today [on RLY-2608] show a more favorable safety profile as well as a more favorable efficacy profile."
Roche presented data from a first-in-human trial of Itovebi with fulvestrant at SABCS in 2021. While cross-trial comparisons are imperfect, 14 out of 54 patients with PIK3CA-mutated, HR-positive, HER2-negative metastatic breast cancer in that study, or 26 percent, had a partial response to Itovebi. The clinical benefit rate was 48 percent, and median progression-free survival was 7.1 months. The rate of any grade hyperglycemia was 62 percent, and 22 percent of patients had grade 3 or higher hyperglycemia.
Wolf also pointed out that Roche's first-in-human trial primarily enrolled second- and third-line patients, whereas Relay tested RLY-2608 on a more heavily pretreated group and that patients had higher rates of diarrhea, rash, and stomatitis in Roche's trial.
The US Food and Drug Administration approved a combination of Itovebi with Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) and fulvestrant for patients with advanced PIK3CA mutated, HR-positive, HER2-negative breast cancer in October based on results from the Phase III INAVO120 trial. Patients on Itovebi-Ibrance-fulvestrant in that study had a median progression-free survival of 15 months compared to 7.3 months on Ibrance-fulvestrant. The objective response rate in the group that received Itovebi was 58.4 percent compared to 25 percent in the control group. The rates of all-grade hyperglycemia and grade 3 or higher hyperglycemia were 58.6 percent and 5.6 percent, respectively.
Unlike RLY-2608, which selectively targets only the mutant form of PI3Kα, Itovebi is an inhibitor of wild-type PI3Kα that is also believed to selectively degrade mutant PI3Kα as a secondary mechanism. Thus, Itovebi marks a transition from traditional PI3Kα inhibitors like Novartis' Piqray (alpelisib) to the next generation of mutant-selective PI3Kα inhibitors showcased at SABCS this year.
Hyperglycemia has been a deterrent to the uptake of Piqray in real-world oncology practice. Data from the Phase III SOLAR-1 trial showed a median progression-free survival of 11 months for patients on Piqray and an overall response rate of 26.6 percent. But the rate of grade 3 or grade 4 hyperglycemia for patients receiving Piqray with fulvestrant in that study was 36.6 percent. As such, doctors and patients alike have been hoping that readouts from studies of next-generation drugs like Itovebi and the newer mutant-specific treatments would show lower rates of grade 3 and higher hyperglycemia.
STX-478's 'high level of pathway inhibition'
At this year's meeting, Scorpion Therapeutics also provided an updated analysis from its Phase I/II trial of the mutant PI3Kα inhibitor STX-478 in advanced solid tumors and announced a new collaboration with Pfizer to develop it with fulvestrant and Pfizer's investigational CDK4 inhibitor atirmociclib in first-line PI3Kα-mutated, HR-positive, HER2-negative metastatic breast cancer. Pfizer and Scorpion will equally share the costs of testing this regimen in a trial, which is slated to begin in the second half of 2025.
In results presented at the symposium from Scorpion's Phase I/II trial, nine out of 43 patients, or 21 percent, with any type of previously treated, advanced PI3Kα-mutated solid tumor responded to STX-478 monotherapy, or to STX-478 plus fulvestrant in the case of HR-positive, HER2-negative breast cancer patients. In the breast cancer subset, five out of 22 patients, or 23 percent, were responders. The disease control rate was 68 percent among breast cancer patients and 67 percent among patients with other solid tumors. The rate of all grades of hyperglycemia among 61 patients was 23 percent, and there were no patients with grade 3 or higher hyperglycemia.
Unlike the RLY-2608 trial, Scorpion's trial included patients who were taking medications to control their diabetes and prediabetes and patients who had discontinued prior PI3K pathway inhibitors due to toxicity. "You had roughly 40 percent of patients with prior PI3 kinase inhibitor exposure," Dejan Juric, an oncologist at Massachusetts General Hospital and lead author on a poster of the STX-478 Phase I/II trial, said during a discussion of the results at the symposium. "You're really stacking the deck against yourself, and despite that, you see the activity. And you have almost half the patients who are prediabetic or diabetic, but still, the drug is tolerable. This tells you that choosing a mutant-selective approach really is a compelling concept."
"Our updated analyses presented at SABCS show STX-478's low-dose modification rates and increased response rate at higher doses, reflecting its high level of pathway inhibition," Scorpion CEO Adam Friedman added in a statement.
Lilly moves on from LOXO-783
Although data from Eli Lilly's Phase Ia/b trial of LOXO-783 demonstrated that hyperglycemia could be minimized through mutant selectivity, 85 percent of patients treated with the compound had diarrhea, which limited the ability of investigators to deliver the optimal preclinical dose in the trial.
LOXO-783 is a highly specific mutant PI3Kα inhibitor targeting only the H1047R mutation. Lilly enrolled patients with PIK3CA H1047R-mutated tumors who had received as many as five prior therapies. Patients with solid tumors on LOXO-783 monotherapy had an overall response rate of 3 percent, a disease control rate of 47 percent, and clinical benefit rate of 16 percent.
Among breast cancer patients on LOXO-783 and their physicians' choice of anti-estrogen therapy, the overall response rate was 6 percent, the disease control rate was 52 percent, and the clinical benefit rate was 52 percent. Lilly also tested LOXO-783 in a triplet combination with anti-estrogen therapy and its CDK4/6 inhibitor Verzenio (abemaciclib). The 18 patients on the triplet therapy had higher response rates including a 100 percent clinical benefit rate.
Because the high rates of diarrhea in the study prevented the drug from being dosed optimally, Lilly is pivoting to a preclinical candidate, LY4045004. In breast cancer xenograft models, LY4045004 demonstrated potent inhibition of mutant PI3Kα while sparing wild-type PI3Kα and other PI3K isoforms. Lilly said it plans to make global regulatory submissions for the new candidate in the first half of 2025.
Discussing the data on the three mutant PI3Kα inhibitors at the symposium, Christos Vaklavas, a breast oncologist at the University of Utah who was not involved in any of the studies, said the results for the three mutant-PI3Kα inhibitors were a step forward for the field "that gives us the opportunity to unfold the true potential of blocking this [PI3K] pathway."
However, he also offered some caveats for the drugmakers and doctors as the compounds advance through clinical trials. "We can hit the target harder, and we can use these drugs in combinations, but there are cumulative low-grade toxicities that may lead to dose reductions, interruptions, and delays," he said. He also speculated that while targeting mutant PI3Kα more selectively may reduce hyperglycemia, that strategy could leave wild-type PI3Kα unchecked as a potential driver of cancer allowing tumor cells to thrive.
MGH's Juric acknowledged that wild-type PI3Kα alpha could become activated either through adaptive mechanisms or genetic alterations. "The single-agent approach, even with these agents, is potentially problematic," he said. "To prevent these adaptive and acquired resistance mechanisms, we will need, at minimum, fulvestrant combinations or other [selective estrogen receptor degrader] combinations" and higher order combinations including other targeted drugs, Juric said. "That's the next frontier, these higher order combinations."
"One thing that we know is you can only derive benefit from a medication that you're able to tolerate and take for a longer time," said Komal Jhaveri, a breast oncologist at Memorial Sloan Kettering and lead investigator on the LOXO-783 study. "The safety profile that we're now beginning to see in these newer generation mutant-selective inhibitors makes them appealing not only to hit the target and avoid the toxicities that we've seen with prior inhibitors that are approved, but also offers this opportunity to go beyond the doublet regimen to even triplet regimens to further do comprehensive blockades."