Sacituzumab Govitecan and Bevacizumab for NSCLC Brain Metastases

Historically, the prognosis for patients with non-small cell lung cancer (NSCLC) brain metastases (BM) was poor, but this paradigm is slowly shifting as current data with an immune checkpoint inhibitor (ICI) based regimen show that a subgroup of patients with BM can achieve long-term survival. For patients with disease progression in the brain after platinum-doublet chemotherapy and ICI, no good systemic treatment options exist and due to local treatments, systemic therapy is often delayed. Of note, most of these patients also have extra-cranial disease progression which needs to be treated. The current standard of care post chemo-ICI progression is docetaxel, with dismal outcomes. The same holds true for patients with NSCLC with an actionable genomic alteration. Upon exhaustion of targeted therapies and platinum-doublet chemotherapy with or without ICI, the standard of care is docetaxel with the same dismal outcomes. Therefore, new systemic therapies that are active systemically as well as intracranially are needed in this population. Antibody-drug-conjugates (ADC) are promising new drugs and several have entered testing in randomized phase III trials. In the majority of the trials evaluating ADCs, patients with untreated BM were excluded. Importantly, Sacituzumab Govitecan (SG), a TROP2-ADC, achieves therapeutic concentrations of SN-38, the active payload of SG, in the CNS. SG is evaluated versus docetaxel in the ongoing EVOKE-1 trial (NCT05089734) but patients with untreated BM are excluded. Preclinically, SG combined with bevacizumab, but not with cetuximab, significantly improved survival over SG alone. Bevacizumab combined with chemotherapy results in an impressive intracranial ORR of 61%. Of note, a possible pseudo response (a marked decrease in contrast enhancement and oedema on MR imaging that often occurs after the initiation of bevacizumab therapy, attributed to normalization of the blood-brain barrier), was not taken into account. Pharmacokinetic drug-drug interactions between bevacizumab and SG are not expected given the distinct proteolytic catabolism responsible for degradation of each monoclonal antibody (moiety). In addition, SN-38 is metabolized by UGT1A1, which is not affected by bevacizumab. Based on the data above, it is of interest to also evaluate SG combined with bevacizumab in patients with BM from NSCLC. This will be evaluated in patients with non-squamous non-small cell lung cancer (NSCLC), with disease progression on chemotherapy and immunotherapy.