Allogeneic Transplant Conditioning Regimens for Patients With Non-Hodgkin Lymphoma

Abstract

In Reply We thank Qi and colleagues for their careful review of our article and their thoughtful comments. We agree that the progression-free survival (PFS) of the osimertinib and bevacizumab combination seen in our study 1 is comparable to the median PFS with osimertinib alone in the FLAURA study. 2 In our article, we note that there was a larger proportion of patients with preexisting brain metastases compared with the FLAURA population (31% vs 19%), and 16% of patients withdrew consent without progression and unrelated to toxic effects to pursue consolidative local therapy (n = 4) or continue with commercial osimertinib (n = 4). These factors may have influenced the PFS in our study.There are historic data that demonstrate that patients with brain metastases have attenuated responses and shorter time on osimertinib therapy as well as other epidermal growth factor receptor tyrosine kinase inhibitors. 3 Similarly, in our study, 1 patients with central nervous system (CNS) involvement had a median PFS of 14.7 months, and those without CNS involvement had a median PFS of 19.2 months (hazard ratio, 0.42; 95% CI, 0.16-1.1). We agree with Qi et al that patients with CNS involvement are a high-risk subset that may benefit from escalation of care. In the upcoming National Cancer Institute phase 3 study of osimertinib vs osimertinib plus bevacizumab (NCT04181060), we will be stratifying for the presence of brain metastases to try to answer this question.We did not see an association between efficacy of the combination and EGFR mutation subtype. Patients with lung cancers that harbor EGFR exon 19 deletions had a median PFS of 18.9 months, and patients with lung cancers with EGFR L858R had a median PFS of 18.4 months (hazard ratio, 0.9; 95% CI, 0.44-1.87). 1 The EGFR mutation subtype does not seem to identify patients who derive the most benefit from combination treatment.We wholeheartedly agree that we need to identify biomarkers that risk-stratify patients to select the appropriate patients for escalation of treatment, such as combination treatment with osimertinib and bevacizumab. One emerging biomarker is circulating tumor DNA (ctDNA) clearance; we discussed in the article 1 that patients with persistent detectable EGFR ctDNA at 6 weeks had shorter PFS and overall survival compared with patients who had clearance of ctDNA, and this has been replicated in other studies. 4 This may be an ideal biomarker to identify patients at risk for early progression who may derive greatest benefit from treatment intensification, and a study using this biomarker to risk-stratify patients receiving first-line osimertinib is currently ongoing (NCT04410796). Patients with persistent EGFR ctDNA after 3 weeks of osimertinib treatment will be randomized to continue osimertinib or add chemotherapy to osimertinib.