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Triplet therapy confers benefit among certain patients with advanced breast cancer
CHICAGO — The combination of ribociclib, everolimus and exemestane conferred clinical benefit and appeared tolerable among patients with endocrine therapy-refractory, hormone receptor-positive, HER2-negative advanced breast cancer that progressed on a CDK 4/6 inhibitor, according to data from the TRINITI-1 trial presented at ASCO Annual Meeting.
“Preclinical evidence suggests that the addition of everolimus (an mTOR inhibitor) to ribociclib (a CDK 4/6 inhibitor) and exemestane (an aromatase inhibitor) may restore sensitivity to both CDK 4/6 inhibitor and endocrine-based therapy,” Aditya Bardia, MD, MPH, assistant professor of medicine at Harvard Medical School and one of the study’s co-authors, told HemOnc Today.
The phase 1/phase 2, multicenter, open-label TRINITI-1 trial evaluated triplet therapy with ribociclib (Kisqali, Novartis), everolimus (Afinitor, Novartis) and exemestane (Aromasin, Pfizer) among men and postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer who received previous CDK 4/6 inhibitor therapy and up to three lines of therapy. Phase 1 of the trial determined the maximum tolerated dose of the triplet. Phase 2 evaluated the safety and efficacy of the daily regimen of 200 mg or 300 mg ribociclib, 2.5 mg or 5 mg everolimus and 25 mg exemestane.
Ninety-five patients (median age, 58 years; 81% white) who were refractory to endocrine-based therapy and progressed after receiving CDK 4/6 inhibitors were evaluable as of Oct. 24, 2018, including 17 patients in phase 1 and 78 patients in phase 2.
Clinical benefit rate at week 24, per RECIST version 1.1 criteria, served as the primary endpoint, with a predefined threshold of greater than 10%.
Average follow-up was 5.3 months (maximum, 22 months).
The triplet therapy demonstrated a clinical benefit rate of 41.1% (95% CI, 31.1-51.6) at 24 weeks, which was four times the minimum threshold for the study. The disease control rate was 61.1% (95% CI, 50.7-70.9), and the overall response rate was 8.4% (95% CI, 3.7-15.9), including one complete response and seven partial responses.
Median PFS was 5.7 months (95% CI, 3.6-9.1), with a 1-year PFS rate of 33.4% (95% CI, 22.8-44.4).
Researchers noted differences in PFS among patients with certain tumor molecular alterations.
“The most common gene alterations found in circulating tumor DNA at randomization were PIK3CA and ESR1,” Bardia told HemOnc Today. “Among the patients with a PIK3CA or ESR1 mutation, concomitant PIK3CA and ESR1 mutations were detected in 46.7% of patients. Patients with ESR1 or PIK3CA mutations at baseline had a numerically shorter median PFS vs. those with wild-type status.”
Bardia said that adverse events in this trial “were consistent with known safety profiles” of the drugs used in the study.
The most common hematologic adverse events included neutropenia (64.6%), thrombocytopenia (29.2%) and anemia (28.1%). The most common nonhematologic adverse events were stomatitis (41.7%), nausea (31.3%) and diarrhea (27.1%).
Most patients (72.9%) experienced grade 3 or grade 4 adverse events, the most frequent of which included neutropenia (47.9%), decreased white blood cell count (11.5%) and anemia (10.4%).
“TRINITI-1 met its primary efficacy endpoint and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with endocrine-based therapy plus an mTOR inhibitor plus a CDK 4/6 inhibitor in patients with endocrine therapy-refractory, hormone receptor-positive, HER2-negative advanced breast cancer after progression on a CDK 4/6 inhibitor,” Bardia said. “The biomarker data suggest that certain tumor molecular alterations may confer therapeutic advantage, and their presence at baseline may be associated with a better outcome with triplet therapy. Additional research is warranted to guide rational therapy selection.” – by Drew Amorosi
Reference:
Bardia A, et al. Abstract 1016. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Bardia reports consultant/advisory roles with or research funding from bioTheranostics, Genentech/Roche, Immunomedics, Innocrin Pharma, Merck, Novartis, Pfizer, Radius Health, Radius Pharma, Sanofi and Spectrum Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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The development and widespread adoption of biological therapies that extend PFS when added to endocrine therapy for advanced hormone receptor-positive, HER2-negative advanced breast cancer have occurred in a rather short period. With the initial approval of the mTOR inhibitor everolimus in 2012 in the second-line setting, and then, in rapid succession, three different cyclin-dependent kinase (CDK) 4/6 inhibitors in the first- and second-line settings in 2015, there are now several areas of uncertainty regarding optimal sequence and regimens.
The natural history for this category of patients after either first- or second-line CDK 4/6 inhibitor therapy is not known, and standard care still follows established guidelines, even though patients progressing on CDK or mTOR inhibitors could acquire a variety of adaptive or genomic selection alterations. Some randomized CDK trials are now reporting outcomes after the subsequent line of therapy. However, formal outcomes gathered by clinical trials standards are lacking.
Researchers of the TRINITI-1 trial enrolled patients after progression on CDK 4/6 inhibitor therapy (for the phase 2 portion), testing the CDK 4/6 inhibitor ribociclib, mTOR inhibitor everolimus and aromatase inhibitor exemestane. Clinical benefit rate (CBR) — defined as overall response rate plus stable disease for at least 24 weeks — served as the study’s primary endpoint, with the bar set rather low at a predefined primary endpoint threshold of greater than 10%. This was surpassed with a CBR of 41.1% (95% CI 31.1-51.6), but with a modest response rate of 8.4%, median PFS of 5.7 months and 1-year PFS of 33.4%.
Researchers noted a high frequency of ESR1 mutations at baseline, as expected among patients who had mostly received aromatase inhibitor therapy. Other known/putative CDK 4/6 resistance drivers such as loss-of-function alterations in Rb and FAT-1 occurred in 7% to 10% of patients, although it is not clear these were present prior to CDK 4/6 therapy. There was hint that ESR1 and, to a lesser extent, PIK3CA mutations negatively affected PFS, as expected.
Interestingly, the toxicity profile was not that different from either CDK 4/6 or mTOR inhibition experience with the altered dosing schedule of continuous low-dose ribociclib with reduced-dose everolimus (either 300 mg/2.5 mg or 200 mg/5 mg) along with 25 mg exemestane daily. However, this trial was not able to address whether CDK inhibition contributed to the clinical activity, so it is not immediately applicable, but could set the stage for one of many needed studies.
We urgently need an array of specific trials or robust registry/real-world data to understand several critical questions after CDK progression in this new era:
- What are the activity and side effect profiles of mTOR inhibition (for example, compared with capecitabine)?;
- Is there any merit to continuing CDK 4/6 inhibition (or changing agent) and switching endocrine therapy vs. endocrine therapy alone, or in combination with other agents?;
- For patients with PIK3CA mutations, is fulvestrant plus the alpha-selective PI3K inhibitor alpelisib (Piqray, Novartis) the best next move compared with chemotherapy or mTOR-including therapy?;
- Should ESR1 mutation status (and more generally, broader mutational profiles) guide bioendocrine therapy selection?; and
- Is intrinsic sensitivity to endocrine therapy (longer time to relapse from initial endocrine therapy), or sensitivity to first-line endocrine/CDK 4/6 inhibitor therapy (longer PFS) a metric that should inform next treatment options?
These are difficult trials to activate when there is pressure to continue the development of newer drugs in this space, such as AKT, FGFR and BET inhibitors, as well as newer oral selective estrogen receptor downregulators. Hopefully, cooperative groups and consortia along with broadening the number of oncology practices participating in clinical research will address these challenges quickly.
References:
Condorelli R, et al. Ann Oncol. 2018;doi:10.1093/annonc/mdx784.
O'Leary B, et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-18-0264.
Turner NC, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810527.
Im SA, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1903765.
The University of Texas MD Anderson Cancer Center
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