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The INAVO120 trial evaluated inavolisib + palbociclib–fulvestrant vs placebo + palbociclib–fulvestrant in patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer progressing on or shortly after adjuvant endocrine therapy (ET). Inavolisib significantly improved overall survival (OS) (34.0 vs 27.0 mo) and progression-free survival (PFS) (17.2 vs 7.3 mo), with a higher objective response rate (ORR) (62.7% vs 28.0%) and longer DoR (19.2 vs 11.1 mo). Toxicities were manageable but included more hyperglycemia (63.4%), stomatitis (55.3%), GI, and ocular AEs. Bottom line: this triplet sets a new bar for first-line PIK3CA-mutant HR+ MBC, but we’ll need to stay vigilant about metabolic and mucosal side effects as we bring it into practice.

Adding Palbociclib did not help, revealing that there is no need to continue with different hormonal therapy than the one used in first line. It also added more toxicity.

DON’T omit, there is still a benefit, especially in 6-10% patients.

No need for radiation if neoadjuvant therapy led to a complete response in the lymph nodes.

The WSG-KEYRICHED-1 phase II trial evaluated a chemotherapy-free neoadjuvant regimen of pembrolizumab plus trastuzumab and pertuzumab in HER2-enriched early breast cancer, achieving a pathological complete response (pCR) rate of 46.5% (95% CI 31.2–62.6%). No survival data (e.g., EFS or OS) were reported, but the regimen showed an acceptable safety profile with no new cardiac toxicity signals. The chemo-free approach suggests promising potential for de-escalation in this subtype, but we’ll need randomized trials to confirm its efficacy and safety.

The INAVO120 trial assessed inavolisib + palbociclib–fulvestrant vs placebo plus palbociclib–fulvestrant in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, showing significant improvements in progression-free survival (PFS) (15.0 vs 7.3 months) and overall survival (OS) (34.0 vs 27.0 months). The triplet regimen achieved a higher overall response rate (ORR) (62.7% vs 28.0%), establishing it as a potential new standard for this endocrine-resistant population. Notably, side effects like hyperglycemia, stomatitis, diarrhea, and ocular effects were more frequent with inavolisib.

In summary: It did not work in those patients with stages II-III.

Metronomic dose: low dose cytotoxic therapy at high frequency was studied in combination with an AI (cape at 500mg TID) and showed superiority over AI single agent, this may be an option for patients not tolerating CKD4/6 inhibitors.

Yet another combination to consider after CDK4/6i + ET in HR+ MBC!

Imlunestrant (novel oral SERD) was active in patients with an ESR1 mutations, but otherwise did not offer a benefit in this population of women with ER+ HER2-neg MBC. Overall survival (OS) data is pending with further follow up.