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Romel Somwar
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 3
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-06 - Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers (ID 1392)
09:45 - 18:00 | Author(s): Romel Somwar
- Abstract
Background
Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after acquiring EGFR T790M on treatment with another EGFR inhibitor. Other studies of osi resistance have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements.
Method
To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had targeted next-generation sequencing (MSK-IMPACT) performed on tumor tissue obtained before treatment and after developing resistance to osi received as either first-line or later line EGFR-TKI.
Result
From January 2016 to March 2019, we collected paired pre-treatment and resistance specimens from 53 patients (1st line osi: 21. Osi after prior TKI: 32). MOR are summarized in the table. Histologic transformation was identified in 18% of 1st line cases and 17% of all cases. When osi was given as initial treatment, with median follow up of 18 months, early emerging MOR rarely included on-target resistance mechanisms (acquired EGFR G724S in 1/21). Other acquired alterations representing potential resistance mechanisms not listed in the table included CCNE1 and MYC amplifications, and mutations in MTOR A1098S and MET H1094Y.
ConclusionFirst line (n = 21)
Osi after prior TKI
(n = 32)
All
(n = 53)
Squamous transformation
3
3
6
Neuroendocrine transformation
1
2
3
On target mutation (EGFR C797X or other)
1
9
10
Loss of EGFR T790M only
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8
8
Fusions (ALK, RET, BRAF)
0
3
3
Amplifications (HER2, MET, EGFR)
2
3
4
Off target mutations (KRAS, BRAF, HER2)
1
2
3
In this analysis of MOR identified on NGS from tumor tissue, we found a spectrum of resistance mechanisms to osi. By evaluating tissue rather than plasma we provide data on histologic transformation (including squamous cell transformation). Subsequent studies are needed to assess patients with a longer time on initial osi as early progressors may have different MOR, with off-target MOR emerging earlier and on-target resistance mutations later.
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P1.14-12 - A Novel Activating MAP2K1 In-Frame Deletion Mediates Acquired Resistance to ROS1 TKIs in a Patient with ROS1 Fusion-Positive NSCLC (ID 2450)
09:45 - 18:00 | Author(s): Romel Somwar
- Abstract
Background
ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib, entrectinib and lorlatinib provide significant benefit in non-small cell lung cancer (NSCLC) patients with ROS1 fusions. As observed with all targeted therapies however, resistance arises. With the widespread adoption of large panel next generation sequencing (NGS) at the time of acquired resistance (AR), our appreciation of novel off-target mechanisms continues to grow. Detecting additional mechanisms of acquired resistance (AR) is crucial to find novel therapies and improve patient outcomes.
Method
We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) of paired pre-treatment and post-progression samples from patients treated with ROS1 TKIs. Genetic alterations hypothesized to confer AR were modeled in a patient-derived cell line (LUAD-0003, expressing EZR/ROS1) as well as isogenic human (HBEC) and murine (NIH-3T3) cell lines. ROS1 fusions were expressed in these cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). Using these cell line models, alterations in drug sensitivity and downstream signal pathways were examined. We also explored possible therapeutic strategies to overcome the drug resistance caused by the novel AR mechanisms examined in this study.
Result
We identified a patient with NSCLC harboring a MAP2K1 (MEK1) variant encoding an in-frame deletion of amino acids E41-L54 (MEK1del) in a sample taken at the time of resistance to lorlatinib (after 9 months’ treatment). This mutation was not detected in the pre-TKI sample. Induction of ROS1 fusions in HBEC and NIH-3T3 cells increased the sensitivity of these cells to ROS1 TKIs and stimulated activation of MEK/ERK signaling in comparison with AKT signaling, suggesting the importance of the RAS-MAPK pathway in driving ROS1 fusion-positive cancers. Underscoring the importance of the RAS-MAPK pathway in ROS1-mediated tumorigenesis, we identified three patients (pancreatic, salivary, and breast cancer) with a ROS1 fusion and NF1 loss-of-function mutation concurrently, in TKI-naïve samples. Expression of MEK1del in HBEC and NIH-3T3 cells harboring ROS1 fusions, and knockdown of NF1 in LUAD-0003, activated ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 (crizotinib, lorlatinib) and MEK (selumetinib, trametinib) inhibited growth of cells expressing both ROS1 fusion and MEK1del.
Conclusion
Our results suggest that the activation of the RAS-MAPK pathway plays a critical role in tumorigenesis mediated by ROS1 fusions, and that activating mutations in this pathway can drive AR to ROS1 TKIs. Combined inhibition of ROS1 and MEK is a potential therapeutic strategy that should be explored clinically.
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P1.14-50 - A Phase 2 Trial of Cabozantinib in ROS1-Rearranged Lung Adenocarcinoma (Now Available) (ID 2753)
09:45 - 18:00 | Author(s): Romel Somwar
- Abstract
Background
To date, no ROS1 inhibitor is approved for the treatment of ROS1-rearranged lung cancers after progression on crizotinib. Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.
Method
In this single-center, open-label, Simon two-stage, phase 2 study, eligible patients had ROS1-rearranged unresectable/metastatic non-small cell lung cancer, a Karnofsky performance status >70%, and measurable disease. ROS1 fusion was identified by local testing in a CLIA-compliant environment. Cabozantinib was dosed at 60 mg once daily. The primary endpoint was objective response (RECIST v1.1). In the first stage of this trial, 1 response was required to move to the second stage. Secondary endpoints included safety.
Result
Six patients received cabozantinib in the ongoing first stage of this study. All patients had >1 prior ROS1 inhibitor. The median age was 59 years; all were never smokers. The best response to therapy was: 1 partial response (-92%, confirmed), 1 unconfirmed partial response (-31%), and 4 stable disease. All patients had disease regression (-7 % to -92%); no patients had primary progressive disease. The only patient with a confirmed partial response was a patient whose cancer acquired a ROS1D2033N solvent front mutation after crizotinib. None of the other five ROS1 inhibitor pre-treated patients (who did not have a confirmed response) had a known on-target acquired resistance mutation in their cancer. After progression on cabozantinib (9.1 months after therapy initiation), the patient whose cancer harbored the ROS1D2033N mutation acquired a METD1228N kinase domain mutation on paired sequencing of pre-cabozantinib and post-progression tumor. The most common grade 3 treatment-related adverse events were hypertension (50%), and mucositis, palmar-plantar erythrodysesthesia, and hypophosphatemia (each in 17%). Most patients (83%) required a dose reduction.
Conclusion
Cabozantinib can re-establish disease control in ROS1-rearranged lung cancers after progression on a prior ROS1 inhibitor. The first stage of this ongoing trial met its prespecified endpoint for efficacy to move into the second stage. Response was only observed in the setting of a known ROS1 kinase domain resistance mutation.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-26 - Elucidating Mechanisms of Resistance to Targeted Therapies in Mutant EGFR or KRAS Driven Lung Adenocarcinoma Harboring Dual Loss of p53 and RB1 (Now Available) (ID 2004)
10:15 - 18:15 | Author(s): Romel Somwar
- Abstract
Background
Inactivation of the two canonical tumor suppressors, p53 and RB1, is a genetic hallmark of small-cell lung cancer (SCLC). In contrast, lung adenocarcinomas (LUADs) preferentially harbor alterations in the p16 pathway over RB1. Nonetheless, despite being rare, concurrent loss of p53 and RB1 occurs in a subset of LUADs and this is hypothesized to be necessary for the histological transformation of LUAD to SCLC, observed during treatment with tyrosine kinase inhibitors (TKIs). However, whether the dual loss of p53 and RB1 is sufficient for this histological transformation remains unknown. Furthermore, loss of RB1 in LUADs with EGFR mutations is associated with poor response to TKIs in the absence of SCLC transformation. Here, we aimed to explore how loss of p53/RB1 affects the biology of p16 pathway-altered LUAD, particularly in the context of acquired resistance mechanisms to targeted therapies.
Method
Four TP53-mutated LUAD cell lines were used: two EGFR mutation-positive (PC9 and H1975) and two KRAS mutation-positive (H1792 and H358). All these cell lines possess p16 pathway alterations: p16 (CDKN2A) mutations in PC9 and H1975, CDK4 amplification in H1792, and silenced p16 in H358. Inactivation of RB1 was carried out using CRISPR-Cas9 and RB1 knockout monoclonal cells were established. Cell proliferative and clonogenic abilities were assessed. In addition, osimertinib-resistant (PC9 and H1975) and trametinib-resistant (H1792 and H358) cells were generated (initial high dose and/or stepwise dose escalation methods). Acquired resistance mechanisms were evaluated by MSK-IMPACT profiling.
Result
Two RB1 knockout clones were established for each cell line. No advantageous effects were observed for proliferative and clonogenic abilities after RB1 knockout. Although loss of p53 and RB1 has been reported to result in lineage shift in prostate cancer through the upregulation of SOX2, deregulation of SOX2 expression was not observed upon RB1 knockout in the TP53-mutant LUAD cells. In addition, although loss of RB1 caused a modest reduction in osimertinib and trametinib sensitivities of H1975 and H358 cells, respectively, no effect was observed in PC9 and H1792 cells. After becoming resistant to osimertinib or trametinib, transformation to SCLC was not observed. Individual resistance mechanisms are currently being assessed by MSK-IMPACT.
Conclusion
Dual loss of p53 and RB1 caused no advantageous effects in TP53-mutated and p16 pathway-altered LUAD cells and did not initiate transformation to SCLC as a resistance mechanism to targeted therapies. TP53/RB1 deficiency-related acquired resistance mechanisms to osimertinib or trametinib will be further explored and presented.
