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G.V.V. Scagliotti
Moderator of
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MS 22 - Variety in the Oncogene (Does the Exact Mutation Matter?) (ID 40)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 4
- Moderators:R.C. Doebele, G.V.V. Scagliotti
- Coordinates: 9/09/2015, 14:15 - 15:45, Mile High Ballroom 4a-4f
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MS22.01 - EGFR Mutations (e.g., Exon 18 vs. 19 vs. 20 vs. 21) (ID 1945)
14:20 - 14:40 | Author(s): D.B. Costa
- Abstract
- Presentation
Abstract:
The most common epidermal growth factor receptor (EGFR) mutations identified in lung adenocarcinomas – termed classic somatic EGFR kinase domain mutations – occur as small inframe deletion (indels) mutations within exon 19 (45% of EGFR mutations, the most common delE746_A750) or the exon 21 L858R (40% of EGFR mutations) point mutation. Tumors harboring these classic EGFR mutations become addicted to EGFR’s signaling cascades and are susceptible (i.e., have a favorable therapeutic window) to inhibition by ATP-mimetic reversible (1[st] generation) EGFR tyrosine kinase inhibitors (TKIs) and C797-covalent (either wild-type specific [2[nd] generation] or mutation specific [3[rd] generation]) EGFR TKIs. EGFR-exon 19 deletions or EGFR-L858R are predictors of radiographic response and progression-free survival when gefitinib, erlotinib (1[st] generation) and afatinib (2[nd] generation) are used for patients with advanced lung adenocarcinomas. These anti-cancer compounds are approved by regulatory agencies and have revolutionized evidence-based care of advanced lung cancer. However, the palliative benefits of these drugs are limited by acquired mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation (which in turn can be inhibited by 3[rd] generation TKIs: mereletinib/AZD9291 and rociletinib. Both of these drugs are undergoing rapid development as palliative therapies for EGFR exon 19 deletion or L858R plus T790M mutated lung cancer and will soon be approved for evidence-based clinical care). The median survival of patients with EGFR-exon 19 deleted or EGFR-L858R mutated lung adenocarcinomas usually exceeds 24-36 months with a substantial portion of patients living for longer than 3 years when given sequential EGFR TKI therapy plus evidence-based cytotoxic chemotherapy. Consistently, patients with EGFR exon 19 deletion mutated lung adenocarcinomas have improved outcomes on 1[st] and 2[nd] generations EGFR TKIs than those with L858R mutated tumors (for biological and clinical reasons that remain to be elucidated). Other EGFR mutations have also been linked in preclinical models and in patients with lung adenocarcinomas to sensitivity to 1[st] and 2[nd] generation EGFR inhibitors. These include exon 18 point mutations in position G719 (G719A, C or S [3% of EGFR mutations]), inframe exon 19 insertions (1% of EGFR mutations), the exon 20 S768I mutation (<1% of EGFR mutations) and the exon 21 L861Q mutation (2% of EGFR mutations). Since most data for response to EGFR TKIs for these less frequent EGFR mutated lung adenocarcinomas comes from retrospective studies or single center experience; the true response rate, progression-free survival and overall survival of these tumors when given gefitinib, erlotinib, afatinib and 3[rd] generation EGFR TKIs is not clear. Interestingly, G719X, L858R and L861Q TKI-sensitive mutations can be commonly identified in conjunction (i.e., complex/compound mutations in >15% of cases) with other less well-defined EGFR kinase domain mutations (such as E709X, L747X, S768X, R776X, T790M, A871G, among others); and these double mutations may affect some of the single mutant pattern of response to EGFR TKIs. In the absence of formal regulatory approval for G719X, exon 19 inserted and L861Q mutated lung adenocarcinomas (groups that comprise more than 5% of all EGFR mutated tumors), the use of EGFR TKIs is often provided as “off label therapy” with clinical management similar to EGFR-exon 19 deletions or EGFR-L858R mutated lung adenocarcinomas. How often EGFR-T790M emerges as a mechanism of resistance in these tumors is unclear. The third most common and most diverse group of EGFR mutations are EGFR exon 20 insertions mutations (up to 10% of all EGFR mutations), which usually occur near the end of the C-helix within the N-lobe of the kinase, after residue M766 up to amino-acid C775, but a small subset map to the middle of the C-helix affecting amino-acids E762 to Y764. Unlike the other aforementioned EGFR mutated lung adenocarcinomas, most tumors with EGFR exon 20 insertion mutations are insensitive (i.e., do not respond radiographically or clinically) to 1[st] and 2[nd] generation EGFR TKIs; with the exception of EGFR-A763_Y764insFQEA (identical to D761_E762insEAFQ and with structural homology similar to exon 21 single mutants by inducing a N-terminal shift in the C-helix while replacing the active site residue E762 of EGFR), where responses to 1[st] and 2[nd] generation EGFR TKIs arise. Preclinical models – that mirror clinical behavior – have convincingly demonstrated that Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD and H773_V774insH are not inhibited by clinically-achievable doses of gefitinib, erlotinib or afatinib. The structure of D770_N771insNPG (a representative EGFR TKI-insensitive exon 20 mutation at the most common insertion position D770_N771) has disclosed the amino acids inserted lock the helix in its active position but don’t alter the kinase domain TKI biding pocket (i.e., these mutants lack a therapeutic window to TKIs when compared to wild-type). Therefore, EGFR exon 20 insertion mutations affecting amino-acids Y764 to V774 should be classified as non-sensitizing to EGFR TKIs and development of mutation-specific TKIs may be hampered by the lack of therapeutic window of the kinase domain when compared to wild-type EGFR. Most EGFR exon 20 insertion mutated lung adenocarcinomas – in lieu of innovative clinical trials – should be treated with evidence-based approaches for “oncogene negative” lung adenocarcinomas. In conclusion, EGFR mutations comprise a heterogeneous group of activating oncogene mutations that have become the most clinically-relevant “driver” oncogenes for the clinical care of lung adenocarcinomas.
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MS22.02 - ALK, ROS1, and RET - Does the Partner Gene Matter? (ID 1946)
14:40 - 15:00 | Author(s): C. Lovly, M. Childress
- Abstract
- Presentation
Abstract:
Chromosomal rearrangements involving the ALK, ROS1, RET, and NTRK1 tyrosine kinases with several different gene fusion partners have been identified as therapeutically actionable genomic alterations in collectively up to 10% of non-small cell lung cancer (NSCLC) [1-4]. Notably, these kinase fusions have also been detected in several other epithelial, hematologic, neural, and mesenchymal malignancies, underscoring the importance of understanding fusion kinase biology in order to develop the most effective therapeutic strategies. In fact, numerous studies have now shown that tumors which harbor ALK, ROS1, RET, or NTRK1 fusions exhibit a dependency on the activated tyrosine kinase for proliferation and survival. This dependency, or ‘oncogene addiction’, makes the cancer highly sensitive to small molecule tyrosine kinase inhibitors (TKIs). In particular, ALK serves as the paradigm for therapeutically targetable kinase fusions in NSCLC. Crizotinib was the first ALK TKI to be approved for treatment of patients with ALK fusion positive (ALK+) NSCLC. Several other ALK TKIs, including ceritinib, alectinib, X-396, brigatinib, ASP3026, and PF-06463922 are also being developed for the treatment of ALK+ malignancies. These ‘next-generation’ ALK TKIs typically have more on-target efficacy against the ALK kinase domain and are able to overcome some of the crizotinib resistance mutations which have been observed clinically. While much emphasis has been placed on the study of the tyrosine kinase portion of ALK, ROS1, RET, and NTRK1 fusions, less is known about the 5’ gene fusion partners. However, the biology of the 5’ gene fusion partner is essential for driving the expression and function of the kinase fusion. Numerous different 5’ gene partners have been identified for each of the kinase fusions in NSCLC (Table 1). For example, EML4 is the most common fusion partner for ALK in NSCLC; however, KIF5B, TFG, KLC1, PTPN3, STRN, and SQSTM1 have also been identified as ALK partner genes in this disease. To add to the complexity, more than 10 different EML4-ALK fusions have been detected in NSCLC, varying by the extent of the EML4 gene which is fused to ALK. Likewise, numerous gene fusion partners have been described for ROS1, RET, and NTRK1 fusions in lung cancer (Table 1). Although the fusion partners can vary, they share three basic features. First, the promoter of the 5’ fusion partner dictates the expression of the fusion. Second, most fusion partners contribute an oligomerization domain, which can aid in auto-activation of the kinase [5]; although, this has not been verified for all fusion partners. The most common oligomerization domain found in the fusion partners is the coiled-coil domain. EML4-ALK homodimerizes by virtue of a coiled-coil domain in EML4. Disruption of this domain abrogates the ability of EML4-ALK to transform cells [5]. Furthermore, the extent of oligomerization may be important for transformation; some fusions dimerize, trimerize [6], or form tetramers [7]. Lastly, the 5’ gene fusion partner also determines subcellular localization of the fusion, and this can have significant effects on the interaction of the kinase fusion with other cellular proteins, influencing activation, signaling, function, and degradation of the fusion. For example, a thorough structural analysis of the most common EML4-ALK variants found in lung cancer revealed differences in the variant’s function, localization, and sensitivity to HSP90 inhibitors in clinical use [6]. Additionally, for some fusions, subcellular localization controls fusion activation, as is the case for MSN-ALK which congregates at the plasma membrane [8]. While most ALK fusions appear pan-cytoplasmic, others like RANBP2-ALK (perinuclear) and NPM-ALK (nuclear, nucleolar, and cytoplasmic) have different localization, the effects of which have yet to be investigated [9]. Very little is known about how signaling downstream of an ALK fusion may differ from that of a ROS1 or RET fusion in lung cancer. In addition, how different gene fusion partners may affect downstream signaling from a specific kinase fusion also remains an open question. One provocative study of various ALK fusions found in anaplastic large cell lymphoma demonstrated that the fusions were differentially able to activate PI3K and JAK-STAT signaling [10]. Furthermore, the ability of the different ALK fusions to activate PI3K kinase activity correlated with the fusion’s transendothelial migration properties. Overall, this study supports the hypothesis that the specific fusion gene partner defines the activity, signaling specificity, and phenotypic properties of the kinase fusion. Notably, the most commonly employed clinical diagnostics used to detect kinase fusions, including immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), will not specify which fusion partner is present within a tumor. However, as more sophisticated next-generation sequencing technologies come to the forefront of clinical diagnostics, clinicians will not only know that a tyrosine kinase fusion is present, but also to which specific gene partner the kinase is fused At present, there is very little data, all retrospective, to address the question of how a different fusion partner may affect clinical outcomes and disease responsiveness to targeted therapies. This is largely because the trials have used methods, such as IHC and FISH, to define eligibility criteria. In-depth contextual studies in pre-clinical models of lung cancer and in clinical trials in patients with kinase fusion positive disease are lacking; however, further analysis of this issue will allow us to refine the treatment of fusion positive lung cancer on a more personalized level in order to more effectively inhibit tumor growth and understand potential therapeutic resistance mechanisms. References 1. Kwak, E.L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010. 363(18): p. 1693-703. 2. Shaw, A.T., et al., Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med, 2014. 371(21): p. 1963-71. 3. Drilon, A., et al., Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov, 2013. 3(6): p. 630-5. 4. Vaishnavi, A., et al., Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med, 2013. 19(11): p. 1469-72. 5. Soda, M., et al., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007. 448(7153): p. 561-6. 6. Richards, M.W., et al., Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem J, 2015. 467(3): p. 529-36. 7. Zhao, X., et al., Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol, 2002. 9(2): p. 117-20. 8. Tort, F., et al., Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest, 2001. 81(3): p. 419-26. 9. Chiarle, R., et al., The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer, 2008. 8(1): p. 11-23. 10. Armstrong, F., et al., Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells. Oncogene, 2004. 23(36): p. 6071-82.Table 1: Spectrum of tyrosine kinase fusions detected to date in NSCLC
Kinase Gene Fusion partner ALK EML4 KIF5B KLC1 PTPN3 SQSTM1 STRN TFG NTRK1 CD74 MPRIP ROS1 CCDC6 CD74 CLTC EZR FIG GOPC LIMA LRIG3 MSN SDC4 SLC34A2 TPM3 RET CCDC6 CUX1 KIAA1468 KIF5B NCOA TRIM33
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MS22.03 - MET - Gene Amplification vs. Overexpression vs. Exon 14 Skipping (ID 1947)
15:00 - 15:20 | Author(s): R. Salgia
- Abstract
- Presentation
Abstract not provided
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MS22.04 - KRAS - Are All KRAS Mutations the Same? (ID 1948)
15:20 - 15:40 | Author(s): T.E. Stinchcombe
- Abstract
- Presentation
Abstract:
KRAS mutations are the most commonly detected mutation in non-small cell lung cancer (NSCLC). KRAS mutations encode proteins containing a single amino acid substitution and in NSCLC most mutations are in codons 12 and 13. KRAS mutant proteins are constitutively activated leading to stimulus independent activation of the RAF-MEK-ERK pathway. KRAS mutations are associated with a history of tobacco use, and are more common in adenocarcinoma than in squamous histology. Patients with history of never smoking have a higher rate of transition mutations, but the biological and clinical significance is unknown.[1]KRAS mutations are mutually exclusive with EGFR mutations and ALK and ROS1 rearrangements. The benefits of testing for KRAS mutations are to eliminate the need for further molecular testing and to enroll patients in trials investigating KRAS directed therapy. KRAS mutational status is predictive of benefit of anti-EGFR monoclonal antibodies in advanced colorectal cancer (CRC), and the benefit is restricted to patients with KRAS wild-type CRC. However, patients with metastatic CRC with KRAS G13D mutations have better prognosis and benefit from monoclonal antibodies demonstrating that the specific KRAS mutation may have clinical implications.[2]KRAS mutational status is not predictive of benefit of cetuximab in advanced NSCLC.[3] The frequency and distribution of KRAS mutation subtype differs significantly among different cancer types. KRAS mutations can activate multiple downstream signaling pathways and activation of signaling pathways may be cancer-specific. The implication is that the success and failures of targeted agents against KRAS pathway in other cancers may not be relevant for the development of KRAS pathway targeting agents in NSCLC. A target therapy is not currently available for KRAS mutant NSCLC, and the recent focus has been on the development of MEK inhibitors. A randomized phase II trial of docetaxel alone or with selumetinib revealed that patients assigned to the selumetinib arm experienced a statistically significant higher objective response rate (ORR) (37% vs. 0%, p<0.0001) and longer progression-free survival (PFS) (hazard ratio of 0.58, 80% CI, 0.42-0.79, p=0.014; median 5.3 and 2.1 months respectively) and a numerically longer overall survival (OS) (HR of 0.80, 80% CI, 5.6 to 1.14, p=0.21; median 9.4 and 5.2 months, respectively).[4] A phase II trial compared trametinib to docetaxel in patients with KRAS mutant NSCLC. The ORR was same in the two treatment arms (12%), and the PFS similar (HR of 1.14; 95% CI, 0.75 to 1.75; p=0.5197).[5,6] Trametinib was also investigated in two separate phase IB/II trials in combination with docetaxel or pemetrexed; patients with both KRAS mutant and wild-type NSCLC were enrolled. Patients with KRAS mutant and wild-type NSCLC had similar ORR and PFS raising the question if KRAS mutations are predictive of MEK inhibitor benefit. In a subset analysis of the trial of trametinib and docetaxel patients with KRAS G12C mutations (n=8) had an ORR of 40% and a disease control rate of 80%.[7] This subset analysis is hypothesis generating and illustrates the need to collect the specific KRAS mutations in trials of novel agents. The prognostic and predictive value of KRAS mutations was investigated in a pooled analysis of resected patients enrolled in adjuvant chemotherapy trials.[8] In the observation cohort no difference OS based KRAS mutational status or subtype was observed, and KRAS mutation status and mutation subtype was not prognostic. In the adjuvant chemotherapy cohort no significant OS benefit was observed among patients with KRAS wild-type and KRAS codon 12 mutant NSCLC; a detrimental effect of adjuvant chemotherapy on OS was observed among the 24 patients with KRAS codon 13 mutant NSCLC (HR of 5.78; 95% CI, 2.06-16.2; p<0.001; interaction p=0.002). This observation needs to be prospectively validated in a larger sample before being used to make decisions about the adjuvant chemotherapy. Preclinical data suggest that the presence or absence other mutations other than KRAS may impact the efficacy of selumetinib.[9]KRAS mutations are frequently found in patients with a significant smoking history, and tobacco related NSCLC is associated high rate of mutations.[10] Thus, the potential impact of concurrent mutations or molecular alterations should be considered in future investigations. 1. Dogan S, Shen R, Ang DC, et al: Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 18:6169-77, 2012 2. De Roock W, Jonker DJ, Di Nicolantonio F, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812-20, 2010 3. O'Byrne KJ, Gatzemeier U, Bondarenko I, et al: Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 12:795-805, 2011 4. Janne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38-47, 2013 5. Blumenschein GR, Smit EF, Planchard D, et al: MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC). Journal of Clinical Oncology 31:abstract 8029, 2013 6. Kelly K, Mazieres J, Leighl NB, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Journal of Clinical Oncology 31:abstract 8027, 2013 7. Gandara DR, Hiret S, Blumenschein GR, et al: Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Journal of Clinical Oncology 31:abstract 8028, 2013 8. Shepherd FA, Domerg C, Hainaut P, et al: Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 31:2173-81, 2013 9. Chen Z, Cheng K, Walton Z, et al: A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483:613-7, 2012 10. Lawrence MS, Stojanov P, Polak P, et al: Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214-8, 2013
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Author of
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)
19:40 - 19:45 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM
Methods:
In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1
Conclusion:
In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.
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MINI31.14 - PROs with Ceritinib in ALKi-Naive ALK+ NSCLC Patients with and without Brain Metastases (ID 1528)
19:45 - 19:50 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), demonstrated sustained clinical activity in ALKi-naive patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). ASCEND-3 (NCT01685138) evaluated patient-reported outcomes (PROs) as well as clinical outcomes with ceritinib, in ALKi-naive ALK+ NSCLC patients with and without baseline BrM.
Methods:
Adult patients with ALK+ NSCLC previously treated with up to 3 lines of cytotoxic therapy received oral ceritinib 750 mg daily. PROs were assessed using Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30, QLQ-LC13) quality of life and lung cancer surveys at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
Of 124 enrolled patients (median age [range] 56 [27–82] years; 40.3% male), 50 (40.3%) had BrM at baseline. At data cutoff (27 June 2014), median follow-up was 8.3 months. Up to cycle 9, PRO questionnaire compliance was at least 97.0%. In the overall patient population, investigator-assessed disease control rate (DCR) was 89.5% and median duration of response (DOR) 9.3 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 86.0% [73.3, 94.2] and 91.9% [83.2, 97.0], respectively, while DOR [95% CI] was 9.1 [7.5, Not Estimable] and 10.8 [9.3, 10.8] months, respectively. Mean change from baseline in patients’ total LCSS score ranged from -3.4 to -11.4 while receiving ceritinib, with 82.1% of patients experiencing symptom improvement; symptoms improved in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS in the full patient population and in the subgroups of patients with and without baseline BrM. In general, mean global quality of life (QLQ-C30) was maintained on treatment for all patients. Patients reported diarrhea and nausea and vomiting symptoms were worse than baseline, however, nausea and vomiting symptoms did reduce over time. Figure 1
Conclusion:
In ALKi-naive patients with ALK+ NSCLC, treatment with ceritinib demonstrated clinical efficacy and improved cancer symptoms, with health-related quality of life generally maintained regardless of baseline BrM status. Improvements were greatest for the lung-related symptoms, cough and pain.
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ORAL 04 - Adjuvant Therapy for Early Stage Lung Cancer (ID 99)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 2
- Moderators:E. Vallieres, Y. Ohe
- Coordinates: 9/07/2015, 10:45 - 12:15, 205+207
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ORAL04.03 - Preliminary Results of the International Tailored Chemotherapy Adjuvant Trial: The ITACA Trial (ID 1262)
11:07 - 11:18 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
In resected early stage (II-IIIA) non-small cell lung cancer (NSCLC) adjuvant chemotherapy improves overall survival but the benefit is limited and pharmacogenomics tailored treatment is a potential way to further improve outcome. A phase III multicenter randomized trial comparing adjuvant pharmacogenomics-driven chemotherapy, based on thymidylate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA NSCLC recently completed patients’ (pts) enrolment (EudraCT #: 2008-001764-36).
Methods:
The mRNA ERCC1 and TS expression by qRT-PCR was centrally assessed on paraffin-embedded, post-surgical tumor specimens in all registered pts. Immunohistochemistry (IHC) straining for ERCC1 (using 2 monoclonal antibodies, 8F1 and 4F9) and TS protein expression was also performed. Randomization was stratified by stage and smoking status. Trial was emended on February 2011 to include the 7th staging system. The primary end point of the study is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. Study design was already reported [Novello S et al, JTO 2013; 8 (Suppl 2) P3.12-023].
Results:
Enrolment was concluded in August 2014 and at that time all gene expression data were available. Recruitment and gene expression results were completed in August 2014. 386 pts were included in the control arm, 375 in the tailored arm and 41 were excluded as screening failures (14) or are not yet fully evaluable (27). Statistical correlations to compare treatments received, toxicity profiles and pts’ survival data in the tailored and control groups are ongoing. Further data analyses will include the correlation between biomarker ERCC1/TS mRNA and protein expression levels, as well as compare ERCC1-IHC scores with the 2 ERCC1 antibodies. The distribution of some baseline characteristics depending on the molecular profile is shown in Table 1. Figure 1
Conclusion:
This trial will provide robust evidence if a tailored therapeutic strategy based on selected gene expression profile may contribute to improve efficacy and to ameliorate toxicity of adjuvant chemotherapy in completely resected early stage NSCLC.
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ORAL04.08 - Discussant for ORAL04.05, ORAL04.06, ORAL04.07 (ID 3468)
12:01 - 12:11 | Author(s): G.V.V. Scagliotti
- Abstract
- Presentation
Abstract not provided
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-057 - Gemcitabine plus Platinum versus Other Platinum Doublets in Squamous NSCLC (ID 149)
09:30 - 09:30 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
Squamous cell carcinoma is the second most common histologic subtype of non-small-cell lung cancer (NSCLC). Platinum-based doublet chemotherapy regimens remain the basis of front-line systemic treatment. Most studies in NSCLC included all histologic subtypes. Here we present a pooled analysis of gemcitabine in combination with cisplatin or carboplatin, specifically focusing on patients with squamous NSCLC, from three studies for which individual patient data are available. The objective of this analysis was to evaluate the efficacy of first-line gemcitabine plus platinum (GP) compared with other regimens plus platinum (OP).
Methods:
This analysis included squamous NSCLC patients from three randomized, open-label, phase III studies of gemcitabine: 1) gemcitabine plus cisplatin versus etoposide plus cisplatin (n=61), 2) gemcitabine plus carboplatin versus paclitaxel plus carboplatin (n=128), and 3) gemcitabine plus cisplatin versus pemetrexed plus cisplatin (n=473). Patients were grouped into the GP subgroup (n=324) or the OP subgroup (n=338). Efficacy measures included overall response rate (ORR), overall survival (OS), and time to disease progression (TTP). Stratified (by study) Cox proportional hazard regression models were used to analyze OS and TTP by random assignment factors to identify potential prognostic factors and explore their predictive value.
Results:
Baseline characteristics were similar between the GP and OP groups. Median OS was 9.72 months for GP versus 9.33 months for OP (HR=0.898, p=0.223) (Figure 1). There was a significant difference in median TTP (5.52 months for GP versus 4.73 months for OP; HR=0.792, p=0.008) (Figure 2). ORR was 31.5% for GP, and 27.2% for OP (p=0.229). Cox regression model identified three prognostic factors for OS: Eastern Cooperative Oncology Group performance status, prior radiotherapy, and body mass index. Figure 1. Kaplan–Meier estimates of overall survival Figure 1 Figure 2. Kaplan–Meier estimates of time to disease progressionFigure 2
Conclusion:
This pooled analysis further confirmed the efficacy of gemcitabine plus platinum as first-line treatment of squamous NSCLC.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-104 - Lung Cancer Patients Derived Xenografts: Prospective Molecular Profiling and Potential Evaluation of Drug Resistance (ID 1278)
09:30 - 09:30 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
The discovery of “driver mutations” such as the Epidermal Growth Factor Receptor (EGFR) and the Anaplastic Lymphoma Kinase (ALK) has led to a remarkable improvement in the outcomes of lung adenocarcinoma, which accounts 50% of the non-small cell lung cancer (NSCLC) diagnoses. Up today, no druggable molecular targets have been identified for squamous carcinoma or small cell lung cancer, which are still treated with the “one-fits-all” therapeutic approach, as it is for a relevant percentage of adenocarcinomas too. The precise definition of molecular profile and, possibly, the description of predictive factors are research priority in the thoracic oncology field. The vast majority of preclinical data are based on in vitro studies, but cell lines models do not entirely reflect tumour characteristics and are hampered by genetic divergence from primary tumours. Patient derived tumour xenografts (PDTX) are a valuable alternative to closely reproduce tumour biology and to prospectively characterize in vivo mechanisms of cancer growth and therapeutic response. Through the generation of a cohort of lung cancer xenopatients, the project aims to confirm the reliability of such models in this disease and to prospectively characterize its biomolecular features.
Methods:
Metastatic and early stages lung cancer cases are considered for the enrolment. Written informed consent is requested from each patient. Fresh tumour tissue from lung biopsies or lung resections is collected and kept in serum free medium (4° C), embedded in 20% matrigel and subcutaneously engrafted into NSG and NOD SCID mice, within 24 hours from sample collection. The exponentially growing tumours are passaged subcutaneously to other mice for a second passage after which they are archived for subsequent analyses (formalin fixed, snap frozen and RNA later). Each sample from surgical resection is also stored to create a DNA lung cancer bank.
Results:
Fourteen samples from TC-guided lung biopsies and sixty-six from radically resected NSCLC were engrafted in NSG and NOD SCID mice lineage in a 1:1 ratio. Due to the low engraftment rate and high morbidity observed in NGS mice in the first 73 samples, subsequent engraftments and expansions were performed in NOD SCID mice only. The overall engraftment rate in biopsy samples was 0 % in NGS and 7.14 % in NOD SCID mice as opposed to 0 % in NGS and 27,27 % in NOD SCID for surgical samples (50% adenocarcinomas, 44,45% squamous carcinomas and 5,55% sarcomatoid carcinomas). Nineteen samples underwent the second passage: of those, 10 samples have been archived after the second successful passage and will be used for further analyses.
Conclusion:
The trial is still ongoing and a longer follow-up is needed. In biopsy-derived samples, engraftment is deeply limited by the paucity of tissue. The results of this study will possibly confirm the reliability of PDTX in lung cancer and provide prospective biomolecular characterization for different histological types.
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P1.12 - Poster Session/ Community Practice (ID 232)
- Event: WCLC 2015
- Type: Poster
- Track: Community Practice
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.12-002 - International Online Tool for Therapeutic Decision Making in NSCLC (V2.0) (ID 2160)
09:30 - 09:30 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
Practice guidelines in non-small-cell lung cancer (NSCLC) list multiple therapy choices based on levels of evidence but cannot account for variability in patient (pt)-tumor characteristics between individual patient cases. To provide oncologists with expert guidance and feedback on choice of treatment (Tx) for specific pt scenarios, we previously implemented an interactive Web-based decision support tool in 2012, in which oncologist users input specific pt characteristics and selected among treatment options, then compared their selection with that of an NSCLC expert panel for that scenario. (Chow JTO 2015). Here we report data from version 2.0 of this tool, capturing current Tx trends for advanced NSCLC and investigating the impact of this online tool on oncology practitioners.
Methods:
V2.0 was developed based on input from 6 international NSCLC experts who provided Tx recommendations for 1st-line treatment in 96 pt case variations based on histology (nonsquamous vs squamous), EGFR mutational status (positive [+] vs negative [-]), ALK rearrangement (+ vs -), age (< 70 vs ≥ 70 years), performance status (0, 1 vs 2), smoking history (never/former light vs former heavy/current), and pt primary Tx goal (response and survival vs quality of life and low adverse events). As in V1.0, oncologist users input specific pt scenarios, then were prompted for their treatment choice. Once completed, recommendations for that scenario from each of the experts were displayed, and users were prompted to indicate whether the expert recommendations changed their treatment choice. Statistical methods: as previously described (Chow JTO 2015).
Results:
V2.0 oncologist users (N = 218 unique users) contributing 314 unique cases were 87% non-USA, 13% USA. As in V1.0, experts agreed on selection of targeted therapies (TKIs) for cases with actionable EGFR mutations and ALK translocations. Choice of a specific EGFR inhibitor by experts varied depending on region and clinical factors. By comparison, among online users of V2.0, an EGFR inhibitor was selected for 67% of EGFR-mutated cases (n = 78), while an ALK inhibitor was selected for 61% of ALK cases (n = 31). For nonsquamous histology cases without actionable mutations, use of pemetrexed was more common among experts compared with oncologist users (91% vs 48% of case scenarios). In 182 cases entered by users who reported on the impact of expert recommendations, treatment choice was affected in 86% of cases (confirmed in 71%); 5.5% disagreed with expert recommendations and 8% indicated barriers to implementing the recommendations. In comparing overall results from V1.0 (2012) to V2.0 (2014), more oncologist users were likely to select TKIs in both EGFR mutation (49% vs 67%) and ALK translocation (35% vs 61%), with a corresponding decrease in use of chemotherapy. A detailed analysis of expert vs user data will be presented, comparing V1.0 (2012) and V2.0 (2014).
Conclusion:
Expert opinions were largely unchanged between V1.0 and V2.0, while oncologist users increased use of TKIs. Most oncologist users of V2.0 either confirmed or changed treatment choices based on expert recommendations. This online tool can aid decision making, serve an educational purpose, and capture practice trends.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-060 - Non Small Cell Lung Cancer in Women: Identification of Molecular Biomarkers Towards Sex Specific Tailored Treatments (ID 1272)
09:30 - 09:30 | Author(s): G.V.V. Scagliotti
- Abstract
Background:
Lung cancer is the leading cause of cancer mortality in both men and women in more developed countries, with a four-fold increase in lung cancer in women in US over the past 30 years. This was confirmed in Europe where, in the last 5 years, lung cancer mortality fell in men (−6%) and increased in women (+7%). Several studies documented sex differences in lung cancer in terms of clinical presentation, survival, pathological patterns and treatment related toxicities; younger age at diagnosis, higher frequency of adenocarcinoma histology, different metabolism of tobacco-related carcinogens, differential gene expression are commonly seen in women. Furthermore, previous studies showed in female gender the expression of functional aromatase enzyme in lung tumor tissues as well as the interaction between Estrogen Receptors (ERs) and Epidermal Growth factor Receptor (EGFR) pathways in lung cancer cells. The aim of this study is to collect a prospective series of advanced stage non small cell lung cancers (NSCLC), to identify, through the Next Generation Sequencing (NGS) technology, potential gender sex differences of selected tumor-associated genes, assessing their both mutational status and gene expression levels.
Methods:
One hundred patients, including 50 women and 50 men, with newly diagnosed stage IV NSCLC will be prospectively enrolled. Smoking history, clinical and anamnestical data will be collected for all patients. Female patients will also provide obstetrical-gynecological anamnesis, while men will provide urological one, if present. Formalin fixed, paraffin embedded diagnostic sample of each patient will be collected and sectioned to obtain: a DNA genomic library to define the mutational profile of a selected panel including 50 tumor-associated genes, a mRNA library to obtain gene expression levels of the corresponding transcripts and protein expression of estrogen receptor Beta (ERß) and DNA repair enzyme ERCC1. Immunohistochemistry reaction, for both ERCC1 and ERβ, will be scored according to the H-score method. NGS analyses will be performed by means of the Ion Torrent Personal Genome Machine (PGM, Life Technologies, Grand Island, NE). Tumor tissues will be tested with commercial library kits: Ion AmpliSeq Cancer Hotspot Panel v.2 to investigate 50 cancer-associated genes and significant gene variations will be further confirmed using Sanger Sequencing method; Ion AmpliSeq™ RNA Cancer Panel to define also gene expression of the same 50 cancer-associated genes (Life Technologies). Correlations among mutational profile, transcriptional pattern, protein levels and clinico-pathological characteristics will be assessed.
Results:
Not Applicable
Conclusion:
Lung cancer incidence in women is increasing worldwide and genetic predisposition, sex hormones or specific molecular features could all account for the clinical differences observed between females and males. Up to the current date, the clinical approach to lung cancer treatment does not rely on gender. The identification of differential status of specific biomarkers can deepen knowledge on the molecular basis of this disease, guiding clinicians towards sex-based treatments.
