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MS 25 - Novel Molecular Targets (KRAS/MET/Novel Fusions): Druggable or Not? (ID 547)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
MS 25.02 - KRAS-Targeted Therapy or Angiogenesis: Still a Viable Target? (ID 7760)
14:30 - 16:15 | Author(s): I. Amanam
NSCLC is a heterogenous disease withvariable molecular mutations. Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is one of the most common oncogenic drivers, especially in lung cancer, found in around 25-30% adenocarcinomas. The other molecular abnormalities related to RAS pathway are EGFR (10-23%), BRAF (2%), MET (2%), HER2 (1%) and NRAS (0.2%). Within KRAS, the most common mutations are G12C (40%), G12V (21%), G12D (17%), G12A (10%) and other (12%) G12 and G13 mutations [Dogan. Clinical Cancer Research 2012; 18: 6169-6177]. KRAS mutations are associated with poorer outcomes in NSCLC. Renaud et al, showed that KRAS mutant patients had worser outcomes compared to wild type cases. KRAS may be a negative predictor of responsiveness to cytotoxic therapy based off of retrospective data. In addition, Renaud and colleagues have shown that KRAS mutations may be predictive of resistance to radiation therapy. Identifying ways to target these KRAS mutations may lead to benefit for patients in combination with other traditional means of treatment. Directly blocking RAS activity has remained difficult to attain, due to a variety of mechanisms and yet to demonstrate efficacy clinically. Therefore, much more focus has been spent on downstream targets of KRAS. Selumetinib an oral inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 had promising phase II results in combination with docetaxel in comparison to docetaxel alone. Unfortunately, in the multicenter Phase III, SELECT-1 trial with 510 patients, PFS and OS were no different in the selumetinib and docetaxel arm versus docetaxel alone. This may be in part due to an increase in RAF-depedent MEK phosphorylation that may interfere with its efficacy. Combining inhibitors that target different components or parallel pathways have yielded success in other tumors like melanoma with combination MEK and BRAF inhibition. For KRAS mutant tumors, the PI3K-AKT- mTOR pathway has also been examined as it has been thought it can bypass resistance to MEK inhibition. The combination of MEK in addition to PI3K-aKT-mTOR has yet to yield any clinically impactful results. Inhibtion of the cysteine residue on KRAS G12C, which makes up more than 40% of KRAS mutants, has been shown to have some activity preclinically [2, 3] Our preliminary data shows that, KRAS is frequently associated with co-occuring mutations. The most common of these were TP53 (n=15, 25%), ATM (n=9, 15%), LRP1B (n=9, 15%), ARID1A (n=8, 13%), STK11 (n=8, 13%), ARID1B (n=7, 12%), TERT (n=7, 12%), EGFR (n=6, 10%), RBM10 (n=6, 10%), SPTA1 (n=6, 10%). We still are not clear on the role of co-mutations and their specific function as sensitizers or agents resistance. It was previously shown that KRAS plus TP-53 mutations had impaired response to docetaxel monotherapy. The addition of selumetinib provided substantial benefit in mice models . Also, STK11 mutations in conjunction with KRAS mutant NSCLC has been shown to infer resistance to PD-1/PDL-1 blockade . Lung cancer frequently exhibits upregulation of angiogenesis and has been reported to be associated with a negative prognostic factor. Over the past decade, novel insights into the role of angiogenesis in NSCLC tumor growth and progression have provided a rationale for the development of anti-angiogenic agents. The use of anti-angiogenic agents to treat NSCLC gained clinical interest in 2006, when the results of the Eastern Cooperative Oncology Group (ECOG) Trial 4599 were published in the New England Journal of Medicine and showed for the first-time improved overall survival(OS) and progression-free survival after the addition of bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that inhibits the process of angiogenesis by binding to the vascular endothelial growth factor A (VEGF-A) protein, to treatment with carboplatin and paclitaxel in 878 patients who had recurrent or advanced NSCLC . Since then, no other anti-angiogenic agent (such as sunitinib, sorafenib, etc.) has been able to demonstrate improved OS for patients with lung cancer. This may be in part because the mechanisms of actions for those drugs is completely different from bevacizumab; they work by inhibiting the internal tyrosine kinase domain of the VEGF receptor and are also not completely selective for the VEGF receptor and also hit other targets (such as PDGF, FGFR, etc.) . This may play a role in the increased toxicity for these inhibitors and the subsequent lower OS. Since the recent positive data showing benefit of first-line carboplatin, pemetrexed, and pembrolizumab may lead to expedited FDA approval, the utility of anti-angiogenic drugs may enter a renaissance as a second-line therapeutic option. However, another consideration has to be made in the pursuit of improved anti-angiogenic drugs where the clinical and financial “value” for the patient are factored in clinical decision making. Though the VEGF/VEGFR pathway is seen as a crucial mediator of tumor survival and growth, the treatments currently available are overshadowed by excessive costs and several cost-effective analyses of bevacizumab have shown that the use of the drug can cost up to 350,000 per life-year gained . References 1. Renaud, S., P.-E. Falcoz, M. Schaeffer, et al., Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases. Br J Cancer, 2015. 113(8): p. 1206-1215. 2. Ostrem, J.M., U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. 503(7477): p. 548-51. 3. Patricelli, M.P., M.R. Janes, L.S. Li, et al., Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov, 2016. 6(3): p. 316-29. 4. Chen, Z., K. Cheng, Z. Walton, et al., A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 2012. 483(7391): p. 613-617. 5. Skoulidis, F., M.D. Hellmann, M.M. Awad, et al., STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma, 2017, American Society of Clinical Oncology. 6. Socinski, M.A., ANGIOGENESIS INHIBITION FOR THE TREATMENT OF NON–SMALL CELL LUNG CANCER. CLINICAL ADVANCES IN HEMATOLOGY AND ONCOLOGY, 2016. 14(5): p. 336-338. 7. Goulart, B. and S. Ramsey, A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health, 2011. 14(6): p. 836-45.
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