2024 Top Story in Oncology: Triplet Therapy for HR+/HER2− Metastatic Breast Cancer

Over the past decade, the treatment of HR+/HER2− metastatic breast cancer (MBC) has been transformed by the addition of CDK4/6 inhibitors to endocrine therapy, which has improved both progression-free survival (PFS) and overall survival. This doublet combination therapy has become the standard of care in the US for most patients. However, many patients who progress to metastatic disease are endocrine-resistant, defined as progression within 24 months of starting adjuvant endocrine therapy (primary resistance) or within 12 months of discontinuing endocrine therapy (secondary resistance), and have concomitant poorer prognosis. In these patients, switching from endocrine therapy to fulvestrant (fulv) — a selective estrogen receptor degrader — plus a CDK4/6 inhibitor provides benefits but is clearly less effective than in patients with endocrine-sensitive disease. Additionally, approximately 35% to 40% of patients with HR+/HER2− MBC have a mutation in the PIK3CA gene, which results in altered PI3K activity, driving more aggressive cancers. More effective first-line therapies are needed for this population.

Based on encouraging phase I/Ib data,¹ the phase III, placebo-controlled INAVO120 trial tested the combination of the selective PI3Kα inhibitor inavolisib and the CDK4/6 inhibitor palbociclib (palbo) plus fulv compared with palbo/fulv alone in patients with PIK3CA mutations and endocrine resistance.² This patient population had a high tumor burden, with 80% of patients exhibiting visceral disease. Circulating tumor DNA testing prior to treatment was performed by liquid biopsy using blood samples. The triplet regimen resulted in a median PFS duration of 15.0 months compared with 7.3 months with the standard palbo/fulv combination. The landmark analysis at 18 months revealed that 46% of patients receiving inavolisib were free of progressive disease compared with 21% of control patients. The objective response rates were 58.4% for patients in the inavolisib triplet arm and 25.0% for control patients. The overall survival data were still immature in this study; however, they tended to favor the inavolisib regimen, with a hazard ratio of 0.64 (95% CI, 0.43–0.97; P = .03, not statistically significant as per the analysis plan). All subgroups benefitted, with the exception of patients aged >65 years and those who had been previously treated with both an aromatase inhibitor and tamoxifen.

These results are impressive but do require some context. The control group performed poorly compared with comparable groups of patients with PIK3CA mutations treated with palbo/fulv in PALOMA-3, where the PFS duration was 10.9 months.³ However, the patients in INAVO120 likely had a more extensive tumor burden and visceral metastases, which are known as poor prognostic factors. Triplet therapy predictably results in more toxicities than palbo/fulv alone, with approximately half of the patients experiencing stomatitis, hyperglycemia, and diarrhea and a quarter of patients experiencing rash. Grade 3 toxicity was far less common, with stomatitis occurring in 5.6%, hyperglycemia in 5.6%, and diarrhea in 3.7%. The occurrence of febrile neutropenia, although rare at 2.5%, was fourfold higher than that observed in the control arm. The dose intensity of all three agents was preserved, and few patients required dose reductions or treatment discontinuation, demonstrating the ability to provide all three agents at full dose in general.

Who should receive this therapy now that inavolisib has been approved by the FDA for use in combination with palbociclib and fulvestrant on October 10, 2024?

Younger patients with HR+/HER2− endocrine-resistant disease who have experienced treatment failure while on adjuvant aromatase inhibitor therapy or within 12 months of treatment cessation and who have a known PIK3CA mutation and multiple organ and/or visceral involvement are excellent candidates for the new triplet therapy. The approval of inavolisib underscores the critical importance of determining the tumor mutational status at the time of diagnosis of metastatic disease, as it is now immediately actionable if a PIK3CA alteration is discovered. Comprehensive genomic profiling, performed using either tissue or blood samples via liquid biopsy, reveals not only PIK3CA mutations but also ESR1, PTEN, and AKT mutations, all of which may be actionable with targeted therapy in subsequent lines of therapy.

Caution should be taken with patients who did not meet the entry criteria, specifically those with diabetes or prediabetes with an elevated hemoglobin A1c level. Additionally, patients with BMIs of ≥30 experienced increased toxicity from the inavolisib regimen and should have aggressive treatment of their hyperglycemia and very close follow-up. The lack of benefit from inavolisib in older patients requires more studies, and, given its toxicity, I would be careful when evaluating the potential risk/benefit ratio in this population. There are no data on re-treating with inavolisib and palbo, as used in this combination, in the increasing number of patients who receive abemaciclib or ribociclib in the adjuvant setting and subsequently experience a recurrence; caution is also advised in this case. Finally, the study did not test an alternative treatment sequence with a PI3K inhibitor after progression on first-line doublet therapy. However, it is well-established that, with each subsequent line of therapy, many patients drop out and do not receive active treatment, potentially depriving them of the benefit of inavolisib or another targeted inhibitor.

The combination of inavolisib, palbo, and fulv is a new and effective treatment for patients with high-risk HR+/HER2− MBC, and it is a welcome addition. Treatment choices in this space continue to expand, offering increased benefit and renewed hope for this largest subgroup of patients with MBC.