MET and EGFR as biomarkers for amivantamab in overcoming RET TKI resistance

2022

Partner Awards

Grant title (if any)

The Hamoui Foundation/LUNGevity Lung Cancer Research Award Program

Tejas Patil, MD

University of Colorado Denver, AMC and DC

Denver

Two possible pathways that seem to be important for resistance to RET inhibitors are the EGFR and MET signaling pathways. Conventional methods of detecting EGFR or MET resistance may not identify many cases where both pathways are involved. In this study, Dr. Patil will use several different laboratory techniques to better detect and define EGFR and MET resistance. He anticipates that the EGFR and MET pathways can be blocked by a newer drug called amivantamab, which is a bi-specific antibody that specifically targets both EGFR and MET.

Research Summary

Improved understanding of the genetics of non-small cell lung cancer (NSCLC) has led to the recognition that certain mutations in NSCLC can be effectively treated with targeted therapy. Unlike chemotherapy, targeted therapy interferes with how a cancer grows and spreads by blocking a specific mutation that a cancer cell needs to survive. An important mutation in NSCLC is the RET gene rearrangement. There have been several targeted treatments (such as selpercatinib and pralsetinib) that are highly effective in controlling RET+ NSCLC. While we can achieve durable long-term control with these RET targeted therapies, ultimately resistance is inevitable. An important category of resistance is called bypass signaling. This is when the cancer activates and recruits a different pathway to grow and survive in the presence of a RET inhibitor. Two possible pathways that seem to be important for resistance are the EGFR and MET pathways. Our main hypothesis is that EGFR and MET pathways are recruited by RET+ cancer cells in the presence of a RET inhibitor as a way for the cancer to survive and escape the effects of the targeted treatment. We suspect that the conventional methods of detecting EGFR or MET resistance may not identify many cases where both pathways are involved. In this proposal, we will attempt to use several different laboratory techniques to better detect and define EGFR and MET resistance. We anticipate that the EGFR and MET pathways can be blocked by a newer drug called amivantamab, which is a bi-specific antibody that specifically targets both EGFR and MET. I wrote an investigator initiated clinical trial that has been approved and funded by Janssen. In this clinical trial, we will have a dedicated cohort for RET+ patients and combine amivantamab with their prior RET targeted therapy. We hope this study will provide insights into the nature of EGFR and MET signaling as resistance mechanisms.

Technical Abstract

Patients with RET-rearranged non-small cell lung cancer (RET+ NSCLC) demonstrate dramatic responses to RET tyrosine kinase inhibitors (TKIs). An important category of acquired resistance is through bypass signaling that circumvents the RET pathway altogether. When a dominant pathway (such as the RET fusion) is inhibited by a TKI (such as pralsetinib or selpercatinib), recruitment of bypass signaling can allow the cancer cell to sustain critical oncogenic pathways. We have generated RET cancer cell lines resistant to both pralsetinib and selpercatinib, LC-2/ad (CCDC6-RET) and CUTO42 (EML4-RET), that demonstrate sensitivity to afatinib, suggesting that EGFR activation is a possible mechanism of resistance. Similarly, MET amplification has been observed as an important bypass signal, seen in up to 15% of RET resistant cases. However, this is likely an under-estimate of the true spectrum of MET-mediated resistance. First, there is no consensus on what copy number (or gene-to-centromere ratio) defines MET amplification in the acquired resistance setting. Second, MET amplification is likely one of many potential mechanisms of MET-mediated resistance. Finally, the level of MET signaling needed for cancer cells to survive in the presence of a RET TKIs may be different than if MET was a de novo driver oncogene. Our central hypothesis is that MET and EGFR expression are present at baseline to varying degrees among patients with RET+ NSCLC. The use of RET TKIs selects for cancer clones that efficiently and effectively utilize bypass signaling through pre-existing EGFR and MET pathways where both have been described as mechanisms of resistance in oncogene-driven subtypes of lung cancer. Amivantamab (JNJ-61186372) is an EGFR-MET bispecific antibody that has shown synergistic inhibition of tumor growth when combined with EGFR TKIs such as lazertinib. In the ongoing CHRYSALIS Phase 1/2 study of amivantamab with lazertinib, an objective response rate of 29% was seen among 28 patients who had no identifiable mechanism of resistance to EGFR or MET TKIs. One interpretation is that several patients in this analysis had EGFR or MET signaling as a mechanism of resistance that were not being captured through traditional biomarker assays. We anticipate that a similar scenario will be present among patients with RET+ NSCLC progressing on RET TKIs. I have written an investigator-initiated trial (IIT) titled “A phase 1/2, open label, study of amivantamab (JNJ-61186372) among participants with advanced NSCLC harbouring ALK, ROS1, and RET gene fusions progressing on tyrosine kinase inhibitors without identifiable mechanisms of acquired resistance” that has already been approved and funded by Janssen. This trial will have a dedicated RET cohort that will allow us an opportunity to obtain samples pre and post-amivantamab. This infrastructure will allow us to readily test the relevance of MET and

Key words

Acquired resistance

Adenocarcinoma

Epidermal growth factor receptor (EGFR)

Metastatic

Non-small cell lung cancer (NSCLC)

RET or rearranged during transfection

Stage III

Stage IV

Targeted therapy

MET and EGFR as biomarkers for amivantamab in overcoming RET TKI resistance

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