PracticeUpdate Oncology May 2019

EDITOR’S PICKS 8

Neratinib and Capecitabine for Patients With HER2+ Breast Cancer and Brain Metastases Journal of Clinical Oncology Take-home message • The authors of this study evaluated neratinib plus capecitabine for treatment of HER2-positive breast cancer brainmetastases. PatientswithHER2-positive brainmetas- tases received neratinib 240mg orally once per day plus capecitabine 750mg/m 2 twice per day for 14 days, then 7 days off. The lapatinib-naive patients (n=37) experienced a composite CNS objective response rate of 49%. Lapatinib-treated patients (n=12) experienced a composite CNS objective response rate of 33%. • The study authors conclude that neratinib plus capecitabine is active against refractory HER2-positive breast cancer brain metastases.

COMMENT By Manmeet Ahluwalia MD, FACP U p to 50% of patients with metastatic HER2-positive breast cancer will develop brain metastases, making it a common clinical challenge in this patient population. The authors report their experience with 49 patients treated with neratinib and capecitabine, 37 of whom had received prior CNS-directed therapy but were lapatinib naive and 12 of whom had failed prior lapatinib therapy. The primary endpoint was CNS objective response rate (ORR = complete response [CR] + partial response [PR]) according to composite criteria. PR was defined as 50% or greater reduction in the sum of CNS target-lesion volumes, without new lesions and without CNS progression, clearly wors- ening neurologic status, or increase in corticosteroid dose (for neurologic symptoms). A CR was defined as disappearance of all target lesions plus the other PR criteria. In the lapatinib-naive group, 18/37 patients had a composite CNS ORR (49%; 95% CI, 32–66%); in the lapatinib failure group, 4/12 patients achieved PR (ORR, 33%; 95% CI, 10–65%). By RANO-BM, 9/37 patients (ORR, 24%; 95% CI, 12–41%) reported PR in the lap- atinib-naive group and 2 additional patients had unconfirmed responses that did not persist for 4 weeks or longer. In the lap- atinib-refractory group, 2/12 patients had PR by RANO-BM (ORR, 17%; 95% CI, 21–48%). In the lapatinib-naive group, the median PFS was 5.5 months (range, 0.8–18.8 months), and median OS was 13.3 months (range, 2.2–27.6 months). The results are promising and compare favorably to lapatinib and capecitabine. The limitations of this combination are the relative short duration of response, albeit most of these patients were refractory (having seen CNS-directed therapy), and the toxicity due to diarrhea. Further trials evaluating SRS and neratinib with capecitabine in the first-line setting are being planned to poten- tially improve both response rates and duration of response. This study also highlights the need for standardization of the response criteria to help determine efficacy – RANO BM is an example of the efforts in this direction. A recently held FDA workshop sup- ported such an effort.

By Reshma L. Mahtani DO T he development of effective therapies for the treatment of HER2+ advanced breast cancer metastatic to the brain remains an area of unmet need. In the adjuvant HERA study, CNS relapse accounted for a larger proportion of the sites of initial relapse in the trastuzumab arm compared with control. These data suggest the CNS represents a “sanctuary site” while many patients experience extracranial disease control. The current study was a phase II trial of neratinib and capecit- abine in HER2+ advanced breast cancer, metastatic to the brain. Both lapatinib-naive patients and patients previously treated with were enrolled. In the lapatinib-naive cohort, an impressive CNS ORR of 49% was reported, with a lower RR of 33% reported in those previously exposed to lapatinib (although numbers were small). In December 2018 top-line positive results were announced from the phase III NALA trial, a randomized controlled trial of neratinib plus capecitabine versus lapatinib plus capecit- abine in patients with third-line HER2+ metastatic breast cancer. For the secondary endpoint of time to intervention for symp- tomatic CNS disease (brain metastases), the results of the trial showed that treatment with neratinib plus capecitabine led to an improvement over the combination of lapatinib plus capecitabine (P = .043). Full results from the study are expected later this year and may represent an important new standard treatment option for this subset of breast cancer patients. It is important to note that the combination of neratinib and capecitabine is already currently endorsed as a category 2A NCCN recommendation (CNS guidelines). " Full results from the study are expected later this year and may represent an important new standard treatment option for this subset of breast cancer patients. "

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