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Top Line: Which tyrosine kinase inhibitor is best for metastatic, HER2+ breast cancer? 
The Study: NALA was a phase 3 trial comparing lapatinib + capecitabine (LC) with neratinib + capecitabine (NC) for women with metastatic HER2+ breast cancer after two prior HER2-targeted regimens. Over 600 patients were enrolled. Among those, roughly ⅓ had received prior trastuzumab, pertuzumab, and T-DM1, and 16% had stable, asymptomatic brain metastases. In comparison, prior therapy with all three drugs was required for HER2CLIMB and nearly 50% of those patients had brain metastases. The NC arm showed superior progression-free survival at 1 year (29%) compared to LC (15%), and a clear separation in the PFS curves emerged at 6 months after enrollment. There was no significant difference, though, in overall survival. The PFS benefit appeared to be driven by increased response rate with NC (32.8% vs 26.7%) as well as a longer duration of response (8.5 vs 5.6 months). The PFS benefit was also most apparent among the subset of patients with triple-positive disease. In patients with brain metastases, the cumulative rate of intervention for CNS disease was lower with NC (22.8%) than with LC (29.2%). On the down side, diarrhea was a frequent adverse event and happened twice as much with NC (24%) than with LC (12.5%).
TBL: Neratinib is superior to lapatinib when paired with capecitabine for women with metastatic HER2+ breast cancer. | Saura, J Clin Oncol 2020


  1. NALA commentary from Plenary Session 2.40: Co-primary endpoint of p < 0.1 for PFS and < 0.4 for OS. Only 35% received HP→ T-DM1, which is the optimal regimen prior to enrollment. Therefore, most patients had weaker HER2 directed therapy before enrollment. The difference only separates after the median, and HRQoL is definitely not improved due to diarrhea.

    HER2CLIMB commentary from Plenary Session 2.56: One hundred percent of patients had all three lines of prior therapy. Around 60% of patients had active (new or progressing) brain mets at the time of diagnosis, which were likely candidates for radiotherapy, including around 25% overall with known, untreated brain mets. We know trastuzumab or capecitabine will be unlikely to penetrate the BBB, while tucatinib is a small molecule. Did these patients visit with a thorough radiation oncologist prior to enrollment? No wonder the 1 year PFS was 0% in the control arm - many of these patients likely should have been irradiated. https://soundcloud.com/plenarysession/ep256#t=1:35


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