Middleton et al. Page 2466

Paradoxically, patients with melanoma and lung cancer harboring BRAF V600E mutations respond to combined BRAF/MEK inhibition, although patients with colorectal cancer (CRC) harboring the same mutation do not. Two transcriptional subtypes of BRAF V600E-mutant CRC (BM1 and BM2) have been described, with BM1 associated with poor prognosis. Middleton and colleagues sought to determine the impact of BM subtyp. on response to combination dabrafenib, trametinib, and panitumumab (D+T+P) in patients with CRC. Patients with the BM1 subtype of CRC responded more favorably to this regimen and showed evidence of immunologic enrichment in their tumors compared with patients with BM2 CRC. These data suggest that further subtyping may be necessary to derive maximum benefit from targeted cancer therapies.

Atkins et al. Page 2506

Patients with metastatic renal cell carcinoma (mRCC) generally have a poor prognosis and frequently experience treatment-associated toxicity. To better understand the impact of treatment on health-related quality of life (HRQOL) in patients with mRCC, Atkins and colleagues assessed patient-reported outcomes (PROs) from the phase III IMmotion151 trial. Patients were previously untreated and received either atezolizumab plus bevacizumab or sunitinib, one of the current standards of care for this disease. Patients who received atezolizumab plus bevacizumab reported a reduced treatment burden, including better overall daily functioning and HRQOL and better tolerated treatment-related side effects than those who received sunitinib. Furthermore, more favorable PROs correlated favorably with progression-free survival. These results further support the clinical benefit of atezolizumab plus bevacizumab for patients with mRCC.

Dagogo-Jack et al. Page 2535

Patients with ALK-positive non-small cell lung cancer, despite initially responding, ultimately develop resistance to this treatment strategy. Furthermore, resistance to the third-generation ALK inhibitor, lorlatinib, is often due to ALK-independent mechanisms. Dagogo-Jack and colleagues identified MET amplification in 15% of tumor biopsies from patients who relapsed following treatment with next-generation ALK inhibitors and detected novel ST7-MET rearrangements in two cases. MET amplification and/or fusion of MET with ST7 decreased sensitivity of ALK-positive cells to ALK inhibitors, and combined blockade of ALK and MET overcame this resistance. Consistent with these in vitro findings, two patients with ALK-positive lung cancer and acquired MET alterations responded to combined inhibition of ALK and MET. This study justifies the further study of ALK/MET combination therap. in patients developing resistance to ALK inhibition.

Recondo et al. Page 2615

Tyrosine kinase inhibitors (TKIs) are expected to become a standard treatment option for patients with non-small cell lung cancer harboring mutations in MET exon 14. However, acquired resistance to these agents hinders their ultimate efficacy, and the molecular mechanisms of resistance remain poorly understood. Recondo and colleagues assessed genomic alterations occurring at the time of progression on MET TKIs via next-generation sequencing of plasma and/or tissue. Genomic alterations known or suspected to be mechanisms of resistance were detected in most resistant patients, including on-target mutations in MET and off-target alterations in KRAS, EGFR, HER3, and BRAF. Two patients who developed on-target resistance mutations demonstrated second partial responses after switching between type I and type II MET TKIs. These results provide rationale for monitoring on- and off-target alterations in patients treated with MEK inhibitors.