Professor Yang Hu Xichun deeply interpreted the results of the second interim analysis of the monarch 3 study total survival

*For medical professionals only

From September 9 to 13, 2022, the European Society of Oncology (ESMO) Conference was held

In the live broadcast room of "A Little Unmeditated Yang" on the evening of September 13, Professor Hu Xichun of the Affiliated Cancer Hospital of Fudan University made an in-depth interpretation

For more live content of "A Little Bit of Medical Yang", please check the video

Deeply rooted in HR+/HER2- breast cancer, Abecilli has obtained a number of indications

Breast cancer is the first cancer that threatens women's health in China, according to the International Agency for Research on Cancer (IARC), according to the International Agency for Cancer (IARC), about 416,000

Abexil is a CDK4/6 inhibitor

In patients with HR+/HER2-advanced breast cancer, the MONARCH 2 study has demonstrated that abexili plus fulvestrant second-line therapy significantly prolongs progression-free survival (PFS) and OS ^[2], whereby the FDA approves abexili plus fulvestrant in patients

SECOND INTERIM ANALYSIS OF THE MONARCH 3 STUDY OS: THE CLINICAL BENEFIT OF ABECILY COMBINED WITH NSAI IN THE OS IS MORE THAN ONE YEAR

MONARCH 3 is a randomized, double-blind, placebo-controlled Phase III study of 493 postmenopausal patients

Figure 1 PFS data from the MONARCH 3 study design

At present, CDK4/6 inhibitors combined with AI have become the standard of first-line treatment for postmenopausal
HR+/HER2-advanced breast cancer.

In the prospective PALOMA-2 study (piperberisil + letrozole), the MONALEESA-2 study (ribesilir +letrozole), and the MONARCH 3 study (abexil + NSAI), CDK4/6 inhibitors combined with AI all met the primary study endpoint and significantly prolonged PFS ^[3-5].


However, the OS benefits were not consistent in the three studies
.

The MONALEESA-2 study did not achieve statistical differences in OS in the previous mid-period analysis, but a significant OS benefit (12.
5 months) was observed in the final OS analysis (median follow-up of 80 months)^[6], while the final OS data from the PALOMA-2 study (median follow-up of 90 months) did not achieve statistical differences ^[7].


The results of the second interim OS analysis of the MONARCH 3 study (median follow-up of 70.
2 months) were presented at the ESMO conference, and Abecily + NSAI had a more than one-year OS clinical benefit (12.
6 months).


The study is still ongoing follow-up, with a final OS analysis
expected in 2023.

It is important to note that in addition to PFS and OS data, ORR is also an important consideration in clinical evaluation of
drug efficacy.

From the MONARCH 3 study, MONARCH plus and other MONARCH series studies, it can be observed that the ORR of Abecili + NSAI treatment can reach more than
60%.

Moreover, indirect comparisons with the PALOMA-2 study and the MONALEESA-2 study found that in the MONARCH series of studies, the absolute value of the ORR resulted in a greater increase in Abexili treatment, which meant a higher proportion of patients benefiting
from it.

Specifically, in the MONARCH 3 study, the Abecilli group increased the absolute orr value by 15.
5% (61.
0% vs 45.
5%) compared to the control group; In the MONARCH plus study, the absolute orr of the Abecilli group increased by 29.
8% (65.
9% vs 36.
1%); In the MONALEESA-2 study, the absolute value of the Liepacilli group ORR increased by 15.
7% (54.
5% vs 38.
8%); In the PALOMA-2 study, the piperacilie group increased absolutes by 10.
9% (55.
3% vs 44.
4%)
.

In addition, the HR values of os in the PALOMA-2 study, the MONALEESA-2 study, and the MONARCH 3 study were 0.
956, 0.
76, and 0.
754
, respectively.

Indirect comparisons show that the HR values of the MONARCH 3 study and the MONALEESA-2 study were comparable or even lower
.

Thus, in the MONARCH 3 study, abexili + NSAI not only extended the clinical benefit of median OS by more than 1 year compared with placebo + NSAI, but also had an HR value as low as 0.
754
.

The current OS data is not yet mature, does not reach statistical differences, and may be closely related to
study design.

The MONARCH 3 study was designed to segment the overall α of 0.
05 across the ITT population and the visceral transfer subgroup, resulting in a smaller
α value in the ITT population.

If there had been no loss of α values, the OS benefit of the ITT population may have been statistically different by the time the study conducted the second interim OS analysis
.

Furthermore, in terms of sample size, the MONARCH 3 study enrolled 493 patients compared to the 668 patients in the MONALEESA-2 study and 666 patients in the PALOMA-2 study^, which means that the MONARCH 3 study needed longer follow-up times to obtain more robust OS data
.

The small sample size combined with the small α value makes it more
difficult to obtain a positive result for the study.

All in all, the final OS results of the MONARCH 3 study are expected to be released
next year.

However, from the available data, including ORR, PFS, OS, and HR values, regardless of whether the final OS result is negative or positive, abexili + NSAI should be considered as a first-line treatment option
for patients with HR+/HER2-advanced breast cancer.

Expert Profiles

Professor Hu Xichun

Director of the Department of Oncology, Fudan University Affiliated Cancer Hospital

Executive Deputy Director of Clinical Trial Institutions Doctoral Supervisor

ESMO Breast Cancer Faculty Member

ABC5 panelist

Chairman of the Committee of Multiple Primary and Unknown Primary Tumors of the Chinese Anti-Cancer Association

Vice Chairman of the Oncology Committee of the Oncology Branch of the Chinese Medical Association

Director of Shanghai Chemotherapy Quality Control Center

Vice Chairman of the Breast Committee of the Chinese Association of Research Hospitals

Member of the Standing Committee and Secretary General of the Breast Cancer Committee of the Chinese Anti-Cancer Association

Chairman of the Cancer Rehabilitation and Palliative Care Committee of Shanghai Anti-Cancer Association

Review expert of the Evaluation Center of the State Food and Drug Administration

References:
[1]Goetz MP, Toi M, Huober J, et, al.
MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC).
Ann Oncol.
2022; 33(S7):LBA15.
[2] Sledge GW Jr, Toi M, Neven P, et al.
The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial.
JAMA Oncol.
2020; 6(1):116-124.
[3] Johnston S, Martin M, Di Leo A, et al.
MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
NPJ Breast Cancer.
2019; 5:5.
[4]Hortobagyi GN, Stemmer SM, Burris HA, et al.
Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
Ann Oncol.
2018; 29(7): 1541-1547.
[5] Rugo HS, Finn RS, Diéras V, et al.
Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.
Breast Cancer Res Treat.
2019; 174(3):719-729.
[6] Hortobagyi GN, Stemmer SM, Burris HA, et al.
Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.
N Engl J Med.
2022; 386(10):942-950.
[7] Finn RS, Rugo HS, Dieras VC, et al.
Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/ human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2- ABC): Analyses from PALOMA-2.
J Clin Oncol.
2022; 40(17_suppl): LBA1003.
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