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IMPACT OF ADDITION OF CELL CYCLE INHIBITOR, RIBOCICLIB, ON BREAST CANCER SURVIVAL

My involvement in cancer advocacy begun in the early 2000. The Cancer Society of Ghana (CSG) forged strong links with Africa Oxford Cancer Foundation (AfrOx) and later on with the erstwhile UT Bank. Some key persons I worked closely with have passed on. Their memories live on as we continue the advocacy against cancer. Breast cancer happened to be our first major campaign and so any material on breast cancer arouses my deepest interest-it has nothing to do with any affinity for the upper lobes.

It is on this basis that with your kind permission, dear reader, I share this study by Seock-Ah et al published in the New England Journal of Medicine (NEJM) July 25, 2019. The title is “Overall Survival with Ribociclib plus Endocrine Therapy In Breast Cancer”. N Engl J Med 2019; 381:307-316DOI: 10.1056/NEJMoa1903765.

The authors noted that breast cancer is known to be more aggressive and to be associated with a poorer prognosis in younger women than in older women. Yet, the recommended treatment for hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer in premenopausal and postmenopausal patients is generally similar, with the exception of the addition of ovarian suppression in premenopausal women. Ovarian suppression induces menopause in premenopausal patients. Besides, suppression may not be complete, and breast cancer that develops in premenopausal women may have biologic differences from that which develops in postmenopausal women.

Indeed, genetic analyses have revealed differences in molecular alterations of key breast cancer driver genes, tumor-suppressor genes, and genes involved in signaling pathways between premenopausal and postmenopausal patients. Premenopausal patients tend to be underrepresented in clinical trials of breast cancer.

Signaling through cyclin-dependent kinases 4 and 6 (CDK4/6) is known to promote continued cell-cycle progression and growth in cancer. In addition, specific CDK4/6 alterations lead to resistance to endocrine therapy in hormone-receptor–positive breast cancer.

In clinical trials, the combination of ribociclib (new molecule) and endocrine therapy has resulted in significantly longer progression-free survival than endocrine therapy alone in patients with hormone-receptor–positive, HER2-negative advanced breast cancer.

Although multiple trials have shown a significant benefit with CDK4/6 inhibitors plus endocrine therapy with respect to progression-free survival, a significant improvement in overall survival has not been shown.

However, overall survival was numerically higher among patients who received a CDK4/6 inhibitor in addition to endocrine therapy than among patients who received endocrine therapy alone in the PALOMA-3 (Palbociclib: Ongoing Trials in the Management of Breast Cancer–3) trial. It has been acknowledged that showing improvements in overall survival in trials involving patients with metastatic breast cancer may be challenging because of potential crossover between treatment groups and subsequent receipt of active treatments, as well as variability in previous treatment exposures between the groups.

Ribociclib is a selective, orally available inhibitor of CDK4/6. In the MONALEESA-7 (Mammary Oncology Assessment of LEE011’s [Ribociclib’s] Efficacy and Safety–7) trial, ribociclib plus endocrine therapy resulted in significantly longer progression-free survival than endocrine therapy alone.

The MONALEESA-7 trial is an international, randomized, double-blind, placebo-controlled, phase 3 trial comparing ribociclib with placebo, in addition to endocrine therapy, in premenopausal or perimenopausal women with hormone-receptor–positive, HER2-negative advanced breast cancer.

Patients were randomly assigned, in a 1:1 ratio, to receive ribociclib (at a dose of 600 mg, administered orally once daily for 21 consecutive days, followed by 7 days off, for a complete cycle of 28 days) or matching placebo. Both groups received goserelin (at a dose of 3.6 mg, administered subcutaneously on day 1 of each 28-day cycle). Patients also received either a nonsteroidal aromatase inhibitor (letrozole at a dose of 2.5 mg or anastrozole at a dose of 1 mg) or tamoxifen (at a dose of 20 mg), administered orally once daily continuously. The choice of endocrine therapy was made based on the patient’s previous adjuvant or neoadjuvant therapy or investigator or patient preference. Crossover between the two groups was not permitted.

Eligible women 18 to 59 years of age, were premenopausal or perimenopausal at the time of trial entry, and had histologically or cytologically confirmed hormone-receptor–positive, HER2-negative advanced breast cancer. Patients were required to have locoregionally recurrent or metastatic disease that was not amenable to curative therapy.

Patients who had received adjuvant or neoadjuvant endocrine therapy were permitted to enroll. Previous endocrine therapy in the context of advanced disease was not permitted, but patients could have received tamoxifen or an aromatase inhibitor within 14 days before randomization or goserelin within 28 days before randomization for advanced breast cancer. These patients continued treatment with goserelin plus the same hormone agent. Patients who had received no more than one previous line of chemotherapy for advanced disease were also eligible. Previous treatment with a CDK4/6 inhibitor was not permitted.

Randomization was stratified according to the presence or absence of liver or lung metastases, previous chemotherapy for advanced disease (yes or no), and endocrine therapy (tamoxifen plus goserelin or an aromatase inhibitor plus goserelin). All patients as well as all investigators who administered treatment, assessed outcomes, and analyzed data were unaware of the group assignments.

The primary end point was investigator-assessed progression-free survival. The secondary end point was overall survival defined as the time from randomization to death from any cause.

A pre-specified exploratory analysis was conducted to assess progression-free survival during receipt of second-line therapy. This was defined as the time from randomization to the first documented disease progression while the patient was receiving second-line therapy (as reported by the physician) or death from any cause, whichever occurred first.

The time to subsequent chemotherapy was defined as the time from randomization to the beginning of the first chemotherapy after discontinuation of the trial regimen. Adverse events were monitored throughout the trial and were graded accordingly.

In this trial, the addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone in patients with hormone-receptor–positive, HER2-negative advanced breast cancer. The overall survival benefit with ribociclib in the subgroup of patients who received aromatase inhibitors was similar to that in the overall intention-to-treat population, and the benefit was maintained across most patient subgroups. The overall survival results were consistent with those of progression-free survival. 

Because overall survival and post-progression outcomes are key factors in clinical decision-making, the results of adding biologic treatments to endocrine therapies in early lines of therapy are highly relevant in this patient population. Additional analysis of progression-free survival while patients were receiving subsequent therapy indicates that the benefit of ribociclib was seen over the combined period of first-line and second-line therapies.

The significantly longer progression-free survival in the ribociclib group than in the placebo group in the previous report of the MONALEESA-7 trial and the approximately 29% lower risk of death in the ribociclib group in this report showed that there was a substantial clinical benefit of ribociclib plus endocrine therapy as compared with endocrine therapy alone.

No new concerns regarding toxic effects were noted with longer follow-up.Because overall survival and post-progression outcomes are key factors in clinical decision making, the results of adding biologic treatments to endocrine therapies in early lines of therapy are highly relevant in this patient population.

The findings were also presented at the annual meeting of the American Society of Clinical Oncology, showed that the addition of cell-cycle inhibitor ribociclib increased survival rates to 70 percent after three and a half years.The mortality rate was 29 percent less than when patients, all under 59 and pre-menopausal, were randomly assigned a placebo.

DR EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC

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