Metastatic HR+/HER2- Breast Cancer
Roche presented the primary results from Cohort B of the IPATunity130 randomized phase III trial, which evaluated Ipatasertib (IPAT) + paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered hormone receptor-positive (HR+) HER2- negative advanced breast cancer (aBC). In the study, it has been observed that the median PFS by independent review committee was 9.2 mo with IPAT + PAC vs. 8.5 mo with PBO + PAC (HR 0.79, 95% CI 0.56–1.13).
In both arms, the objective response rate was 47%, and the median response duration was 9.2 mo. Overall survival (OS) results are immature (deaths in 25%). Median PAC duration was 6.9 mo with IPAT + PAC vs. 8.8 mo with PBO + PAC; the median duration of IPAT was 8.0 mo, and PBO was 9.1 mo. IPAT + PAC was associated with more AEs leading to the withdrawal of PAC (26% vs. 13%) or IPAT/PBO (11% vs. 4%).
The study showed that adding IPAT to PAC did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ aBC. The IPAT + PAC safety profile was consistent with the known AEs of each agent. OS follow-up is ongoing.
Novartis presented the data of SOLAR1 trial at ESMO 2020. In phase III SOLAR-1 trial of pts with progression on/after aromatase inhibitor (AI), the PI3Kα inhibitor ALP together with FUL significantly improved progression-free survival (PFS) in the PIK3CA-mutant (mut) cohort (HR 0.65; 95% CI 0.50-0.85; P<0.001; median [m] PFS 11.0 mo with ALP + FUL vs 5.7 mo with placebo [PBO] + FUL), a population with poor prognosis. At the final PFS analysis, the first interim OS results were immature.
The study showed that, in the patients with PIK3CA-mutant (mut) cohort, mOS was 39.3 months in the alpelisib Arm vs 31.4 n the placebo arm. This means that the mOS was significantly prolonged by 7.9 months for the patients in Alpelisib arm. The median time to chemotherapy (TTC) was also prolonged with ALP + FUL vs PBO + FUL. Coupled with the statistically and clinically significant PFS, these data further support ALP + FUL in this poorer prognostic population of pts with PIK3CA-mut ABC.
Lilly presented that data on nextMONARCH study, which was a multicenter, randomized, open-label phase II trial of abemaciclib in women with heavily pretreated HR+, HER2- MBC whose disease progressed on or after ET and chemotherapy.
The study showed that the addition of tamoxifen to abemaciclib provided a statistically significant median OS improvement (7.2 months) compared to abemaciclib monotherapy in this heavily pretreated HR+, HER2- MBC patient population (24.2m vs 17.0m). Final OS analysis occurred 24 months after the last patient entered treatment.
The study also showed that the OS benefit was consistent across subgroups including patients with liver metastasis and those who received prior tamoxifen for advanced/metastatic disease. PFS was consistent with the primary results of nextMONARCH with no significant difference. Also, the incidence and severity of treatment-emergent diarrhea was improved in nextMONARCH (Grade 3:9%) compared to data previously reported for MONARCH1 (Grade3:20%).
Early HR+/HER2- Breast Cancer
ESMO 2020: PALLAS trial
The most awaited results of the Phase III PALLAS trial came out which showed that the addition of Palbociclib to the adjuvant ET did not prolong the iDFS in patients with stage II-III HR+/HER2- breast cancer.
Pfizer initiated PALLAS trial in the adjuvant setting of HR+/HER2- breast cancer to evaluate Palbociclib in combination with Endocrine therapy vs Endocrine therapy alone. Since the CDK4/6 inhibitor with endocrine therapy has shown promising data in prolonging the PFS and OS in the first-line, pre-treated metastatic setting of HR+/HER2- breast cancer with tolerable and acceptable side effects, PALLAS trial was designed to check the combination in the adjuvant setting. A total of 5,760 patients were randomized at 406 sites in 21 countries.
Most patients had stage IIb and stage III disease and had received prior lines of chemotherapy. Nearly 60% of patients had high-risk disease with ≥4 nodes involved or 1-3 nodes with either T3/T4 and/or G3 disease. Within the safety evaluable population, TEAEs occurred in 99.4% of patients in Palbociclib + ET arm vs. 88.6% in ET alone. All grade neutropenia was the most common side-effect in Palbociclib + ET arm with an overall rate of 82.9%. Other all-grade toxicities occurring more often with P included leukopenia, fatigue, thrombocytopenia, anemia, upper respiratory tract infection, and alopecia. At the time of interim analysis read-out with 351 iDFS events, the futility boundary for iDFS was crossed.
The Independent Data Monitoring Committee reviewed this result and subsequently recommended the discontinuation of Palbociclib. At a median follow-up of 23.7 months, no significant differences in iDFS (invasive disease-free survival) (P+ET vs. ET; 88.2% vs. 88.5%) and Distant Recurrence Free Survival (DRFS) (P+ET vs. ET; 89.3% vs. 90.7%) was observed. Subgroup analyses also did not show any clinical benefit for the addition of Palbociclib to the endocrine therapy arm.
The cumulative incidence of palbociclib discontinuation at 6, 12, 18 and 24-months was 17.8%, 29.9%, 38.0% and 45.1% respectively. The majority of Palbociclib discontinuation was related to adverse events (64.2%). About half of the patients required at least one dose reduction of palbociclib, and one-third of patients required two dose reductions. The dose reduction from 125mg to 100mg occurred in the first three months of the treatment.
So, in the PALLAS trial, the addition of palbociclib to the adjuvant ET did not prolong the iDFS in patients with stage II-III HR+/HER2- breast cancer. But the PALLAS story has not ended yet; instead, there is an ongoing analysis in the TRANS-PALLAS translational and clinical research program with almost 6,000 tumor blocks and 10,000 blood samples to understand CDK4/6 inhibition and contemporary management of HR+/HER2- breast cancer.
Early HR+/HER2- Breast Cancer
ESMO 2020: monarchE trial
The highly anticipated results for the Phase III monarchE trial were disclosed at ESMO 2020 which favored the addition of Abemaciclib to the Standard of Care Endocrine Therapy in the adjuvant setting of HR+/HER2- breast cancer
Elli Lilly initiated monarchE trial in the adjuvant setting of HR+/HER2- node-positive, high-risk early breast cancer to evaluate Abemaciclib in combination with endocrine therapy compared with endocrine therapy alone. The primary efficacy endpoint was invasive disease-free survival (iDFS) by STEEP criteria. Abemaciclib, a CDK4/6 inhibitor, is approved in the advanced/metastatic setting of HR+/HER2- breast cancer with tolerable safety and efficacy; the same was explored in the adjuvant setting too.
A total of 5,637 pre-/post-menopausal patients showing no distant metastases with ≥4 positive axillary lymph nodes or 1-3 axillary lymph nodes having tumor size ≥5 cm, histologic grade 3 and centrally tested Ki67 ≥20% were randomized in Abemaciclib+ SOC Endocrine therapy arm (A+ET) vs. SOC Endocrine therapy (ET) arm. The study met its primary endpoint with a p-value of 0.0096 correspondings to the HR (95% CI) of 0.747 (0.598, 0.932), which meant there was a total risk of invasive disease reduction by 25.3%.
In the Kaplan–Meier curve, the two-year iDFS rates were 92.2% for A+ET arm and 88.7% for ET arm alone, which showed an absolute difference of 3.5%. A key secondary endpoint distant relapse-free survival (DRFS) was also met with a p-value of 0.0085 correspondings to HR (95% CI) of 0.717 (0.559, 0.920), which meant there was a total risk of distant recurrence reduction by 28.3%. 2-year DRFS rates as per Kaplan–Meier curve were 93.6% for A+ET arm and 90.3% for ET arm alone which showed an absolute difference of 3.3%. There were major differences seen in distant recurrence locations of bone and liver metastases, which showed 32 patients with bone metastases in A+ET arm and 81 patients in ET arm, whereas 29 patients with liver metastases in A+ET arm and 42 patients in ET arm.
So, monarchE study concluded that the abemaciclib is the first CDK4/6 inhibitor that showed a statistically significant improvement in iDFS when combined with ET compared with ET alone in patients with high-risk HR+/HER2- breast cancer. There was also a reduction in the risk of distant recurrence, particularly in bone and liver metastases, and safety was also consistent with the known profile of abemaciclib. Subsequent result disclosures can give more clarity over the addition of abemaciclib to the SOC endocrine therapy, and if it shows positive results, it may prove to be an emerging SOC for the segment.