Sibylle Loibl, MD presented the final analysis of invasive disease-free survival (IDFS) and overall survival (OS) outcomes from the phase 3 KATHERINE trial of adjuvant ado-trastuzumab emtansine (T-DM1) versus trastuzumab for residual invasive HER2+ early breast cancer (BC) after ≥6 cycles of neoadjuvant chemotherapy and ≥9 cycles of trastuzumab. Patients who typically have poor outcomes were randomly assigned to 14 cycles of either T-DM1 (n-740) or trastuzumab (n=720) within 12 weeks of surgery. The primary analysis was reported in 2018.

At final analysis, median follow-up was 8.4 years. The 7-year landmark IDFS benefit was 13.7% favoring T-DM1 (80.8%) versus trastuzumab (67.1%; HR 0.54; 95% CI 0.44, 0.86; P<.0001). Most IDFS events were distant recurrences, with CNS recurrence less common in T-DM1 (5.1% versus 7.0% for iratumumab).

OS was significantly improved with T-DM1 at 89.1% T-DM1 versus 84.4% for trastuzumab (HR 0.66; 95% CI 0.51, 0.87; P<.0027). Deaths due to BC were more common in the trastuzumab group (15.0% versus 9.5%). The T-DM1 benefits in IDFS and OS were seen for all subgroups. Serious adverse events (AE), grade 3-4 AE, and cardiac toxicity were similar between arms, with no new safety signals seen.

Dr. Loibl concluded that T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2+ early breast cancer with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis.

Komal Jhaveri, MD presented the primary analysis of the phase 3 INAVO120 study of palbociclib plus fulvestrant in combination with either inavolisib (triplet) or placebo (standard of care comparator) in PIK3CA-mutant, hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic BC. More effective treatment is needed for this population as well. 

Inavolisib selectively inhibits PI3Kα and may cause fewer of the safety and tolerability issues seen with other PI3K inhibitors. Patients with PIK3CA mutated, HR+, HER2- ABC were randomly assigned to triplet (n=161) or control (n=164) groups. 

At a median follow-up of 21.3 months, progression-free survival (PFS) was 7.3 months for placebo versus 15.0 months for inavolisib (HR 0.43; 95% CI 0.32, 0.59; P<.0001). Interim OS was 31.1 months for placebo and not reached for the inavolisib group. Duration of response was 18.4 months for the triplet versus 9.6 months for the control arm (HR 0.57 95% CI 0.33, 0.99).

Major AE included hyperglycemia, rash, diarrhea, and stomatitis. Primary prophylaxis was not offered in the trial, and AE were treated at first instance, including antihistamines or rash, dexamethasone mouth wash for stomatitis, and “management skills” for the others. More patients in the triplet arm discontinued due to AE (6.8% versus 0.6% in the placebo arm). 

Discussant Hope Rugo, MD said the INAVO120 study is moving the needle forward in tackling endocrine resistance in high-risk metastatic HR+/HER2- BC and clearly represents a new treatment option. The tight blood glucose control requirements of the trial would exclude many high-risk patients in the U.S. A planned study will evaluate inavolisib in individuals with pre- and type II diabetes, and other studies are ongoing to target PI3K.

Dr. Lederman has no conflicts of interest to report.

Illustration by Jennifer Bogartz