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CHICAGO -- An "adaptive response" treatment strategy identified a subset of patients with HER2-positive early breast cancer who benefited from a chemotherapy-free treatment plan, according to new findings from the phase II trial.

The strategy is based on evaluating an early response to a dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with ¹⁸F-FDG PET imaging and postsurgical pathological complete response (pCR). Among 267 patients in an intention-to-treat [ITT] population, 220 (79.6%) had an early response (based on PET imaging) to 2 cycles of treatment with trastuzumab and pertuzumab, while 86 (37.7%) went on to have a pCR after 6 more cycles of chemotherapy-free treatment, reported Javier Cortés, MD, PhD, of the Ramón y Cajal University Hospital, in Madrid.

Those findings, previously reported in , met one of the trial's two primary endpoints.

In the current analysis, investigators showed that among these 86 patients with a pCR, only one had an invasive event (locoregional ipsilateral recurrence) for a 3-year invasive disease-free survival (iDFS) rate of 98.8% (95% CI 96.3-100.0), Cortés detailed in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

"This strategy might identify 30% of patients who may be cured without the need for chemotherapy, and only treated with a combination of trastuzumab and pertuzumab and endocrine therapy, if appropriate," Cortés said.

Regarding the entire ITT population, which included patients who received some chemotherapy, the 3-year iDFS rate was 95.4% (95% CI 92.8-98.0), thus meeting the study's second primary endpoint with ≤15 patients experiencing an iDFS event (P<0.001). "In my opinion, these results are in line with those reported using the combination of chemotherapy plus double blockade from the very beginning," he noted.

Moreover, Cortés reported that those patients who only received trastuzumab and pertuzumab experienced substantially fewer grade 3 or 4 related treatment-emergent adverse events (TEAEs) than patients who received chemotherapy, "highlighting the extraordinary quality of life of those patients who did not receive chemotherapy."

ASCO discussant Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, observed that the results of the trial are an excellent example of how to use a dynamic imaging marker to "provide a window of opportunity to re-intensify therapy and tackle the issue of safety." He suggested the trial demonstrates the potential value of using PET as an integral marker in other settings as well, such as triple-negative breast cancer.

"Is it potentially practicing changing?" he asked. "I believe with phase III validation that this is a real foundation of a potentially practice-changing finding."

Cortés explained that the development of HER2-directed therapies have not only improved the outcome of patients with HER2-positive early breast cancer, it has lead to the investigation of different de-escalation strategies, such as the one his group evaluated in PHERGain. The randomized, non-comparative trial included 356 patients from sites in Spain, France, Belgium, Germany, and the U.K. Eligible participants were women ages ≥18 with central confirmed HER2-positive, stage I-IIIA, invasive, operable breast cancer, with at least one lesion evaluated by PET.

Patients were assigned to two groups:

• Group A (n=71): Docetaxel at 75 mg/m², area under the concentration-time curve 6 mg/mL per min IV, subcutaneous fixed-dose trastuzumab at 600 mg, and pertuzumab at a loading dose of 840 mg followed by maintenance dosing at 420 mg
• Group B (current analysis): Initially received 2 cycles of trastuzumab and pertuzumab, and endocrine therapy if appropriate

PET scans were performed before patients were randomized and again after two treatment cycles. Patients assigned to group A completed 6 cycles of treatment (every 3 weeks) regardless of PET results.

All patients assigned to group B initially received 2 cycles of trastuzumab and pertuzumab. PET responders continued this treatment for 6 further cycles, while non-responders in this group were switched to 6 cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was performed 2-6 weeks after the last dose of study treatment.

Related TEAEs of any kind occurred in 98.5% of patients in group A, 90.5% in group B as a whole, and 81.4% in patients in group B who did not receive chemotherapy.

In addition, among those patients who only received trastuzumab and pertuzumab, just 1.2% experienced a grade 3 or 4 related TEAE (a case of grade 3 neutropenia) compared with 32.9% of patients in group B as a whole, and 61.8% of patients in group A. Related serious AEs occurred in 0%, 13.8%, and 27.9% of those three groups, respectively.

"As somebody who studies immune-related events in my own lab, while this wasn't unexpected, it was really powerful to see the data of how much more likely the quality of life is for these patients who are saved or spared from chemotherapy," Balko remarked.

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