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S. Yano
Moderator of
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MS27 - Mechanisms of Acquired Resistance to Targeted Therapy (ID 44)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 4
- Moderators:S. Yano, B. Solomon
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
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MS27.1 - Resistance to EGFR TKIs (ID 589)
10:30 - 12:00 | Author(s): S. Yano
- Abstract
- Presentation
Abstract
Dramatic response has been achieved by EGFR inhibitors in lung cancer expressing EGFR activating mutations. However, cancer cells show either intrinsic or acquire resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, and cause disease progression. Known major mechanisms for acquired resistance to EGFR-TKI include T790M gatekeeper mutation in the EGFR gene and activation of bypass survival signal via receptors other than EGFR. The latter mechanism can involve Met gene amplification and ligand-triggered receptor activation as well. For example, HGF, the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant cancer cells. Moreover, common polymorphism in BIM gene was recently reported to be found specifically in East Asian and confer intrinsic resistance to EGFR-TKI. These accumulating evidences suggest that mechanisms of EGFR-TKI resistance are complicated and heterogenous even in one individual. In this session, the resistance mechanisms will be introduced and therapeutic strategies will be discussed.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS27.2 - Resistance to ALK Inhibitors (ID 590)
10:30 - 12:00 | Author(s): R.C. Doebele
- Abstract
- Presentation
Abstract
ALK gene rearrangements occur in approximately 5% of lung adenocarcinomas and less frequently in other histologic subtypes. Crizotinib is currently the standard of care for ALK+ NSCLC (1). Treatment with crizotinib leads to remarkable objective response rates, durable progression free-survival and superiority over standard second line chemotherapy. Unfortunately, patients eventually experience disease progression on crizotinib. Disease progression may occur primarily in the central nervous system (CNS) alone, likely because of poor penetration of crizotinib into this space, or simultaneously with systemic progression outside of the CNS (2). Systemic disease progression likely occurs via cellular resistance that occurs by multiple mechanisms, which have been observed in vitro or in patient tumor samples derived following progression on crizotinib. Mutations in the kinase domain of ALK currently account for approximately 25% of observed drug resistance (3-5). Resistance mutations occur at the ‘gatekeeper’ position, L1196M, but multiple other ALK kinase domain mutations have been observed in patient samples or in cell lines with induced drug resistance. Indeed, in the first case of published crizotinib resistance, the tumor harbored two separate ALK mutations (6). This pattern stands in contrast to EGFR mutant lung cancer, where the observed rate of resistance mutations is 50-60% and the majority of resistance mutations occur at the gatekeeper position, T790M (7). Also in contrast to EGFR mutant lung cancer, resistance mutations in ALK do not appear to confer a fitness disadvantage to the tumor cell (3). Mutations induce resistance by allowing persistent ALK signaling despite the presence of crizotinib. Copy number gain of the ALK fusion has also been observed in both cell line models and in patient tumor samples following crizotinib resistance (3, 4). It is hypothesized that that a fraction of ALK fusion proteins are not inhibited by clinically achievable doses of crizotinib and that increased expression may allow sufficient downstream signaling for tumor cell survival. Collectively, we have termed resistance mutations and copy number gain as ‘ALK-dominant’ mechanisms of resistance, because the tumor cells are still predicted to be ‘addicted’ to ALK signaling. Multiple mechanisms of ‘bypass’ signaling have been observed in both cell line models and post-progression tumor biopsies. These include activating mutations in EGFR and KRAS, and ligand dependent activation of EGFR or KIT (3, 4). In some cases the ALK gene rearrangement is no longer observed in post-crizotinib biopsy, also suggestive of an alternate or bypass signaling pathway. We have termed these bypass signaling mechanisms as ‘ALK non-dominant’ resistance as the tumor cells may no longer be dependent on ALK signaling. Approximately 50% of patients have been shown to harbor each class (dominant vs. non-dominant) resistance and this may have implications for post-progression therapy in these patients (1). Next generation ALK inhibitors such as LDK378, AP26113, and CH/RO5424802 which potently inhibit the ALK kinase and have activity against many of the resistance mutations in vitro, may be the favored post-progression therapy for patients with ALK dominant resistance. All of these drugs have also demonstrated anecdotal evidence of activity in the CNS. Although not ALK-specific, HSP90 inhibitors, such as ganetespib, IPI-504, and AUY-922, can inhibit ALK signaling by decreasing proper folding of the chimeric ALK fusion proteins and may also overcome ALK dominant resistance (8). ALK non-dominant resistance may require dual inhibition of ALK and a bypass signaling pathway to overcome resistance and the selection of drugs would be dependent on the alternate signaling pathway. Currently, no post-crizotinib therapies are approved in ALK+ lung cancer, but systemic chemotherapy remains as useful treatment strategy and some evidence suggests that pemetrexed-based regimens may be an optimal initial choice in the absence of a clinical trial (9). References 1. Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future challenges. Nat Rev Clin Oncol. 2012;9:268-77. 2. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443-5. 3. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-82. 4. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra17. 5. Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, et al. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013. 6. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-9. 7. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 8. Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30:2581-6. 9. Camidge DR, Kono SA, Lu X, Okuyama S, Baron AE, Oton AB, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774-80.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS27.3 - Clinical Definition of TKI Resistance and How to Overcome It (ID 591)
10:30 - 12:00 | Author(s): P.A. Jänne
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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- Abstract
- Presentation
Abstract
Lung cancer therapy in the metastatic setting is invariably characterized by the emergence of resistance. This applies both to conventional chemotherapy and molecular targeted agents. This presentation will focus on the biological background and subsequent trial designs as it applies to resistance regarding molecular targeted agents (MTA). In the clinical setting when a patient develops progressive disease while exposed to a MTA some key basic considerations should be taken into account before considering acquired biological resistance. Compliance of the patient to the prescribed therapy is an obvious one. Indeed chronic exposure to tyrosine kinase inhibitors (TKI) exposes the patient to chronic toxicities. Some of these toxicities can become intolerable for the patient, thus leading to patient-driven therapeutic breaks that are frequently not specified to the clinician. This is notably true for week-end breaks as well holiday breaks. Honest dialogue with the patient is necessary to identify compliance issues and pharmacological (PK) dosage in the blood of the relevant TKI is an approach to be discussed. Further pharmacokinetic interactions represent a real issue with TKI: many TKI are metabolized by the liver and can have CYP liabilities (ie erlotinib, gefitinib are susbtrated of CYP3A4). Inter-individual PK variability due to genotypic background (polymorphisms in genes encoding drug metabolizing enzymes), inflammatory and nutritional status, may result in suboptimal drug concentrations and decreased efficacy. Significant decrease in drug exposure over time have also been described for and may result in secondary progression despite preserved sensitivity to these agents, with a potential role for subsequent dose escalation. From a biological perspective, 3 main mechanisms have been described to explain resistance to TKI: a) mutation/amplification in the target (ie T790M for EGFR or ALK L1196M), bypass mechanism (ie Met amplification, PI3K mutation, HER 3 activation,) and growth survival/apoptosis resistance (ie loss of BIM, SCLC, EMT). Stronger kinase inhibitors and use of combinations appear as potential solutions to deal with these resistance mechanisms. Some of the potential designs to address acquired resistance include: a) upfront combinations, b) use of third generation inhibitors or mutant-specific inhibitors, c) rolling trials (ie the use of sequential TKI therapies), c) alternating therapeutic approaches (TKI followed by chemotherapy or TKI followed by immunotherapy).Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
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MS27 - Mechanisms of Acquired Resistance to Targeted Therapy (ID 44)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 1
- Moderators:S. Yano, B. Solomon
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
-
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MS27.1 - Resistance to EGFR TKIs (ID 589)
10:30 - 12:00 | Author(s): S. Yano
- Abstract
- Presentation
Abstract
Dramatic response has been achieved by EGFR inhibitors in lung cancer expressing EGFR activating mutations. However, cancer cells show either intrinsic or acquire resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, and cause disease progression. Known major mechanisms for acquired resistance to EGFR-TKI include T790M gatekeeper mutation in the EGFR gene and activation of bypass survival signal via receptors other than EGFR. The latter mechanism can involve Met gene amplification and ligand-triggered receptor activation as well. For example, HGF, the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant cancer cells. Moreover, common polymorphism in BIM gene was recently reported to be found specifically in East Asian and confer intrinsic resistance to EGFR-TKI. These accumulating evidences suggest that mechanisms of EGFR-TKI resistance are complicated and heterogenous even in one individual. In this session, the resistance mechanisms will be introduced and therapeutic strategies will be discussed.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
