Predictors of response to CDK4/6i retrial after prior CDK4/6i failure in ER+ metastatic breast cancer

Abstract

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8-16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Fig. 1. CDK4/6i retrial cohorts.

A flow/CONSORT diagram outlining how patients were divided into cohorts for data analysis is shown here. From our 195 total patients, patients were first separated depending upon why their first CDK4/6i regimen was discontinued. Patients who discontinued therapy due to toxicity were considered Cohort 1. The remaining patients (who had stopped initial CDK4/6i due to progression of disease (POD)) were further separated depending upon what type of combination regimen was chosen on retrial. Cohort 2 represented patients who kept the same CDK4/6i but changed endocrine therapy (ET) partner. Cohort 3 represented patients who were treated with a different CDK4/6i. Of note, 14 patients were treated with 3 separate lines of therapy containing a CDK4/6i and therefore were documented as separate treatment instances (treatments 1 and 2 vs treatments 2 and 3). These individual patients ended up in multiple cohorts to account for their multiple treatment instances.

Fig. 2. Median Time to Treatment Failure (TTF).

Median TTF for both first CDK4/6i exposure and CDK4/6i retrial are shown in the table above. Below each cohort is the respective survival curves for CDK4/6i retrial. As noted before, median TTF for retrial in Cohort 1 is substantially longer than median TTF for initial exposure. This relationship is inverted for Cohorts 2 and 3, again speaking to the biological difference between Cohort 1 and Cohorts 2 and 3.

Fig. 3. Cohort 1: Time to treatment failure at first CDK4/6i exposure vs. retrial.

The two-headed swimmer plot for patients in Cohort 1 is shown here. For each patient, both the TTF for initial CDK4/6i exposure (blue, pointing leftward) and for CDK4/6i retrial (pink, pointing rightward) are shown side-by-side. The TTFs for retrial color-coded depending upon the treatment line for metastatic disease corresponding to CDK4/6i retrial. TTF2 (2–3) = 2nd or 3rd line; TTF2 (4–5) = 4th or 5th line; TTF2 (>5) = 6th line and beyond.

Fig. 4. Cohort 2: Time to treatment failure at first CDK4/6i exposure vs. retrial.

The two-headed swimmer plot for patients in Cohort 2 is shown here, using the same notation as Fig. 3. TTF2 (2–3) = 2nd or 3rd line; TTF2 (4–5) = 4th or 5th line; TTF2 (>5) = 6th line and beyond.

Fig. 5. Cohort 3: Time to treatment failure at first CDK4/6i exposure vs. retrial.

The two-headed swimmer plot for patients in Cohort 3 is shown here, using the same notation as Figs. 3 and 4. TTF2 (2–3) = 2nd or 3rd line; TTF2 (4–5) = 4th or 5th line; TTF2 (>5) = 6th line and beyond.

Fig. 6. Genomic alterations in patients with short and long TTF to CDK4/6i retrial in Cohort 3.

Somatic tumor mutation profiles of patients in Cohort 3 that had good response (>9 months TTF) and poor response (<4 months TTF) for CDK4/6i retrial. Each column represents an individual patient, organized first by BOR by PRISSMM criteria then by timing of mutational profile sample (Before first CDK4/6i, In-Between initial exposure and retrial, or After CDK4/6i retrial). RB1 and FAT1 loss of function mutations as well as CDK4 amplifcations were seen exclusively in patients with TTF < 4months. Two patients in the TTF > 9 months had FAT1 mutations that were variants of unknown significance. Other classical ER + MBC resistance mutations, such as those in TP53, PIK3CA, and ESR1 were fairly evenly distributed between the two subgroups.