The MONARCH 3 study’s invited discussant, Meritxell Bellet Ezquerra, MD, PhD, a senior researcher at the Vall d’Hebron Institute of Oncology in Barcelona, commented: “The second interim analysis for overall survival in MONARCH 3¹ indicates a positive trend, which was also observed for the subgroup of patients (at least 50% of the population) with visceral disease. The hazard ratio for the updated progression-free survival (hazard ratio [HR] = 0.518) is even better than that previously reported (HR = 0.540),” she said. “Almost 27% of patients are progression-free in the abemaciclib arm, at a median 5.8 years of follow-up, supporting the likelihood of achieving a definitive overall survival improvement.”

Meritxell Bellet Ezquerra, MD, PhD

As Dr. Ezquerra noted, survival data are now available for the three main CDK4/6 inhibitors: abemaciclib, ribociclib, and palbociclib. Based on these data from MONARCH 3, MONALEESA-2², and PALOMA-2,³ she concluded: “We need a better understanding of tumor biology at disease progression for each CDK4/6 inhibitor, as the progression-free survival achieved with each is ‘strikingly’ similar. Head-to-head comparisons are lacking, but the HARMONIA trial is ongoing.” HARMONIA is comparing ribociclib and palbociclib in hormone receptor–positive, HER2-negative and HER2-enriched subtypes.

Meanwhile, Dr. Ezquerra added: “The choice of CDK4/6 inhibitor remains challenging. Ribociclib has the maximal level of evidence in overall survival in the first-line trials. Abemaciclib may well achieve the same level of evidence next year. Palbociclib is still in the equation: PALOMA-2 was negative, but real-world data support an overall survival improvement. It also has a predictable safety profile and is the partner for most ongoing endocrine studies.” In selecting a drug in this class, Dr. Ezquerra emphasized, the toxicity profile, quality of life, drug-drug interactions, and/or individual patient preferences should always be considered. 

Updated Findings From monarchHER Trial

Results of the monarcHER study⁴ were discussed by Sung-Bae Kim, MD, PhD, of Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Sung-Bae Kim, MD, PhD

Dr. Kim noted the significant improvement in response rate, clinical benefit rate, and progression-free survival when abemaciclib plus trastuzumab was given with fulvestrant, vs chemotherapy and trastuzumab, but not when abemaciclib plus trastuzumab was given without fulvestrant. The numerical trend in overall survival was accompanied by a consistent overall survival benefit across prespecified subgroups, with the pooled abemaciclib arms.

Like previous studies of this drug, grade ≥ 3 diarrhea was seen in 9%, and grade ≥ 3 neutropenia was observed in 27% of patients, noted Dr. Kim. “However, it is worth noting that grade 1 or 2 diarrhea occurred in more than 70% of patients receiving abemaciclib. The bottom line is the safety profile of abemaciclib is generally consistent, with the primary toxicity being clinically manageable,” he said.

As for the differences in progression-free and overall survival observed between luminal and nonluminal subtypes, the more favorable outcomes in patients with luminal-type disease may be the result of their better inherent prognosis, he suggested. In addition, he pointed out, with just 65% of the profiles sampled for intrinsic subtype, it is unclear what percentage of samples were coming from the primary or metastatic site. “The triplet’s efficacy needs to be tested in patients with luminal disease alone, rather than in all patients,” he suggested moving forward.

“This chemotherapy-free triplet could be a treatment option for patients with hormone receptor–positive, HER2-positive breast cancer, especially those who are heavily pretreated,” Dr. Kim concluded. “RNA-sequencing analysis may further refine HER2 classification and could be helpful in identifying which patients may be most likely to benefit and in stratifying patients in clinical trials. As for patients with luminal HER2-positive, hormone receptor–positive disease, the focus should be on more effective endocrine-based therapies rather than on chemotherapy.” 

DISCLOSURE: Dr. Ezquerra reported relationships with Pfizer, Novartis, and Lilly and is a member of the SOLTI Executive Board and Scientific Committee. Dr. Kim has received institutional research funding from Novartis, Sanofi-Aventis, and DongKook Pharm Co; has served as a consultant or advisor for Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co Ltd, ISU Abxis, OBI Pharma, Beigene, Daiichi-Sankyo, Legochem Biosciences, HLB Life Science, and Samsung Bioepis; and owns  stock in Genopeaks and NeogeneTC.

REFERENCES

1. Goetz MP, Toi M, Huober J, et al: MONARCH 3: Interim overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor in patients with HR+, HER2– advanced breast cancer. ESMO Congress 2022. Abstract LBA15. Presented September 9, 2022.

2. Hortobagyi GN, Stemmer SM, Burris HA, et al: Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 386:942-950, 2022.

3. Finn RS, Rugo HS, Dieras VC, et al: Overall survival with first-line palbociclib plus letrozole versus placebo plus letrozole in women with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analyses from PALOMA-2. 2022 ASCO Annual Meeting. Abstract LBA1003. Presented June 4, 2022.

4. André F, Nadal JC, Denys H, et al: Final overall survival for abemaciclib plus trastuzumab ± fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER). ESMO Congress 2022. Abstract LBA18. Presented September 10, 2022.