Matched Targeted Therapy Improves PFS Through Multigene Sequencing in Metastatic Breast Cancer

Fabrice André, MD

Genomic alterations identified through multigene sequencing, classified in the I/II tiers of the ESMO Scale of Actionability of Molecular Targets (ESCAT), and paired with matching targeted therapy led to a significant improvement in progression-free survival (PFS) vs maintenance chemotherapy in patients with HER2-negative metastatic breast cancer, according to a pooled analysis of findings from the randomized phase 2 SAFIR02_BREAST (NCT02299999) and SAFIR-PI3K (NCT03386162) trials that were presented during the 2021 San Antonio Breast Cancer Symposium (SABCS).

The results showed that among 115 patients who had an ESCAT I/II genomic alteration, the median PFS was 9.1 months (90% CI, 7.1-9.8) with matched targeted therapy vs 2.8 months (90% CI, 2.1-4.8) with maintenance chemotherapy (adjusted HR, 0.41; 90% CI, 0.27-0.61, P < .001).

“These findings suggest that genomics should be a part of the pathway of care, but it has no impact if the results are not interpreted using a validated framework of actionability of the gene alterations identified,” lead study author Fabrice André, MD, PhD, professor of medical oncology at the Institut Gustave Roussy in Villejuif, France, said in a press release, which was accompanied by a virtual press briefing ahead of the conference.

“Multigene sequencing has been widely implemented, but its clinical impact and the best framework for its use are unclear. The main purpose of our study was to test whether genomic analyses are useful for patients with metastatic breast cancer, and how we can best analyze the results,” André said.

To that end, the open-label, multicentric phase 2 SAFIR02_BREAST and SAFIR-PI3K trials enrolled patients with HER2-negative metastatic breast cancer who were eligible for first- or second-line chemotherapy.

In SAFIR-PI3K, patients with PIK3CA-mutated metastatic breast cancer were randomized to the PI3Kα-specific inhibitor alpelisib (Piqray) plus the estrogen receptor antagonist fulvestrant (Faslodex) or maintenance chemotherapy.

In both trials, patients who had received more than 1 line of chemotherapy or 1 of the targeted therapies evaluated in the trial were excluded from enrollment. If patients had hormone receptor–positive disease, they had to have endocrine-resistant disease.

Patients underwent a pre-treatment biopsy of the metastatic lesion, which was followed by next-generation sequencing and SNP array analysis.

After 6 to 8 cycles of induction chemotherapy, patients without evidence of disease progression (n = 238 of 1462; 16%) who had an actionable genomic alteration were randomized to matched targeted therapy (n = 157) or maintenance chemotherapy (n = 81).

The targeted therapy drugs and matching targets consisted of vistusertib for mTOR, AZD4547 for EGFR, capivasertib for AKT, sapitinib for HER2 or EGFR, selumetinib (Koselugo) for MEK, vandetanib (Caprelsa) for VEGF or EGFR, bicalutamide (Casodex) for the androgen receptor, olaparib (Lynparza) for PARP, and alpelisib for PIK3CA.

The primary end point of the study was to determine whether genomically-driven targeted therapy improved PFS vs maintenance chemotherapy.

Hierarchical testing was applied such that efficacy was tested first in patients who had an ESCAT I/II alteration. If a P value of less than 0.1 was reported in the first analysis, subsequent analysis was conducted in the intent-to-treat population.

ESCAT classification is defined as follows:

• Tier I: Alteration-drug match is associated with improved outcomes in clinical trials
• Tier II: Alteration-drug match is associated with antitumor activity, but the magnitude of benefit is unknown
• Tier III: Alteration-drug match is suspected to improve outcome based on clinical trial data in other tumor types or with similar molecular alterations
• Tier IV: Preclinical evidence of actionability
• Tier V: Alteration-drug match is associated with objective response, but without clinically meaningful benefit
• Tier X: Lack of evidence for actionability

Additional findings reinforced that ESCAT classification was highly predictive for the benefit of matched targeted therapy (interaction test, P = .004). Notably, matched targeted therapy was not effective in patients without an ESCAT I/II alteration (HR, 1.15; 95% CI, 0.76-1.75).

Further findings failed to show a significant difference in PFS between the targeted therapy and chemotherapy arms in the overall population, with a median PFS of 5.5 months (90% CI, 4.0-6.9) vs 2.9 months (90% CI, 2.3-4.8), respectively (adjusted HR, 0.77; 95% CI, 0.56-1.06; P = .109).

Additional findings showed that the SNP array analyses (n = 926) detected 21 genes more commonly altered in metastases vs primary tumors. Of these, focal TERT amplifications were associated with a poor outcome. Focal CDK4 amplifications were found after resistance to CDK4/6 inhibitors.

Finally, high homologous recombination deficiency was associated with prolonged PFS in patients with BRCA mutations who had received olaparib (HR, 0.32; 95% CI, 0.12-0.83; P = .013).

“The general implication of our study is that precision medicine can improve patient outcome if it is interpreted with the right tools,” André said.

“I cannot overstate how important this clinical trial is,” Virginia Kaklamani, MD, a professor of medicine in the Division of Hematology/Oncology at UT Health San Antonio and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, and SABCS codirector and moderator of the press briefing added following André’s presentation of the data.

“This is the first trial that we have where we have used genomic alterations to actively change a patient’s treatment plan and found an improvement in the patient’s outcome. This is for early-stage breast cancer patients, which is even more important because the whole point [of treatment] is to try to prevent metastatic disease,” Kaklamani continued.

“What we’re trying to do and what Dr. André showed so eloquently was that by finding changes in the tumor that were unique to that patient and by having targeted therapies available for that change, we were able to treat the patient with that specific targeted therapy instead of standard of care, which would have been chemotherapy, and improve the patient’s outcome. This [tool] is something that we’re going to be using more and more in practice, [so that we’re] really treating our patients based on [their] genomic alterations,” Kaklamani concluded.

Reference

1. André F, Gonçalves A, Filleron T, et al. Clinical utility of molecular tumor profiling: results from the randomized trial SAFIR02-BREAST. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; virtual. Abstract GS1-10