Matching adjusted indirect comparison shows superior survival with ribociclib vs. palbociclib in first-line HR+/HER2- advanced breast cancer

First-line treatment of HR+/HER2- advanced breast cancer (ABC) consists of a CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). In the absence of direct head-to-head comparisons of the different CDK4/6i, a matching adjusted indirect comparison (MAIC) was used to compare the outcomes from the MONALEESA-2 (ribociclib) and PALOMA-2 (palbociclib) trials. Ribociclib+ET was associated with a significantly greater overall survival benefit compared to palbociclib+ET.

The standard of care for the first-line treatment of patients with HR+/HER2- advanced breast cancer (ABC) consists of the combination of a CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). In this setting, both the MONALEESA-2 (ML-2) and PALOMA-2 (PAL-2) trials looked at first-line treatment with a CDK4/6i (ribociclib and palbociclib, respectively) + ET vs. ET alone in postmenopausal women with HR+/HER2 ABC. Only ML-2 demonstrated a statistically significant overall survival (OS) benefit for ribociclib + ET (HR[95%CI]: 0.76[0.63-0.93]), while in the final analysis of PAL-2, palbociclib + ET did not extend OS in a comparable first-line population (HR[95%CI]: 0.96[0.78-1.18]), compared to ET alone. In the absence of direct head-to-head trial results of ribociclib vs. palbociclib, a matching adjusted indirect comparison (MAIC) is a well-accepted method to compare relative effectiveness of treatments, which accounts for differences in populations between clinical trials. At EBCC 2022, a MAIC comparing progression-free survival (PFS) and OS benefits of ribociclib and palbociclib in the first-line setting was presented, based on the final data cut-off of ML-2 and PAL-2 trials.

ML-2 and PAL-2 study design & comparison

Both ML-2 and PAL-2 investigated the efficacy and safety of a CDK4/6i (ribociclib and palbociclib, respectively) + letrozole vs. letrozole alone as first-line treatment for postmenopausal patients with HR+/HER2-ABC. Study design and patient population characteristics were very similar between the two trials, including a similar proportion of patients with a treatment-free interval of ≤ 12 months.   In total, ML-2 and PAL-2 included 668 and 666 patients, respectively. In this MAIC, individual patient data from the last ML-2 data cut-off (median follow-up of 80 months) were matched to the latest available aggregate PFS and OS data from PAL-2 (median follow-up of 37 months for PFS, 90 months for OS), excluding patients in ML2 who did not meet the criteria for PAL-2. Matched ML-2 individual patient data were re-weighted to match average baseline characteristics of PAL-2 participants. Rescaled weights ranged from 0 to 5.15, with a median of 0.72 for ribociclib + letrozole and 0 to 12.68, with a median of 0.64 for placebo + letrozole. Anchored HRs were generated via the Butcher method.

Results

After balancing and weighting, the effective sample size (ESS) of ML-2 was 150 for the ribociclib arm and 112 for the placebo arm. Baseline characteristics were well-balanced after matching. In each trial, PFS was significantly better with the CDK4/6i + letrozole, when compared to letrozole alone. However, MAIC revealed a numerical PFS advantage for ribociclib + letrozole over palbociclib + letrozole (HR[95%CI]: 0.80 [0.58-1.1], p= 0.187). In the final OS analysis of ML-2, a statistically benefit in OS was demonstrated for ribociclib+ letrozole vs. letrozole alone. In contrast, the final OS of PAL-2 failed to demonstrate an OS benefit with palbociclib + letrozole over letrozole alone. MAIC showed significant OS benefit with ribociclib + letrozole vs. palbociclib + letrozole (HR[95%CI]: 0.68[0.48-0.96]; p= 0.031).

Conclusions

In this MAIC, ribociclib+ letrozole was associated with a significantly greater OS benefit, as well as with a numerically greater PFS benefit, than palbociclib+letrozole as first-line treatment for postmenopausal patients with HR+/HER2- ABC. In light of the ongoing debate on whether patient differences could have influenced the comparison of OS data from the ML-2 and PL-2 trials, the results of this MAIC, which is adjusted for patient-level differences, provide additional data to support the use of ribociclib + letrozole over palbociclib + letrozole as first-line treatment for HR+/HER2- ABC.

Reference

Jhaver K, O'Shaughnessy J , Fasching P, et al. Matching adjusted indirect comparison of PFS & OS comparing ribociclib + letrozole vs palbociclib + letrozole as first-line treatment of HR+/HER2− ABC: Analysis based on updated PFS & final OS results of MONALEESA-2 & PALOMA-2. Presented at EBCC 2022; Abstract ORAL-001.