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D.B. Costa
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)
19:00 - 19:05 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.
Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.
Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1
Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.
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MINI30.09 - Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2913)
19:15 - 19:20 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.
Methods:
We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.
Results:
The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.
Conclusion:
In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)
18:45 - 18:50 | Author(s): D.B. Costa
- Abstract
- Presentation
Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.
Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.
Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.
Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.
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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: 1
- 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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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-023 - A Phase II Trial of AUY922, a Heat Shock Protein 90 (HSP90) Inhibitor, in ALK-Positive Lung Cancer Patients Previously Treated with ALK Inhibitors (ID 1739)
09:30 - 09:30 | Author(s): D.B. Costa
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) fusions are key oncogenic drivers in non-small cell lung cancer (NSCLC) that confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Despite this activity, ALK-positive patients ultimately develop resistance to ALK TKIs. In preclinical models, ALK fusion proteins are HSP90 clients and remain sensitive to HSP90 inhibition despite acquired resistance to ALK TKIs. We therefore designed a phase II trial of the HSP90 inhibitor AUY922 in patients with previously treated, ALK-positive NSCLC.
Methods:
In this single-arm, multicenter, open-label study, we enrolled patients with advanced, ALK-positive NSCLC who had failed at least one prior ALK inhibitor. Key eligibility criteria included ECOG PS 0-2, measurable disease based upon RECIST version 1.1, and presence of an ALK rearrangement by FISH. Participants were treated with AUY922 at a dose of 70 mg/m[2 ]IV once weekly until disease progression, unacceptable toxicity, or death. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Key secondary endpoints included safety, progression-free survival (PFS), and disease control rate (DCR). The planned sample size was 20 patients.
Results:
Between December 2012 and December 2014, 6 patients were enrolled. Median age was 52.5 years (range 42-54 years). A majority of patients (83%) were female. The median number of prior lines of therapy was 3 (range 2-4). All patients had previously received at least 1 ALK TKI (crizotinib n=5, alectinib n=1), and 2 patients had received a second ALK inhibitor (ceritinib n=2). Most patients (n=4) had received an ALK inhibitor as the last line of therapy prior to enrollment. Among the 6 patients enrolled, no objective responses were observed (ORR 0%). Three patients (50%) had a best response of stable disease (SD), but none remained on therapy beyond 3 months from the time of enrollment (Table). The median PFS was 1.43 months (95% CI 1.3-2.8 months). Common adverse events (AEs) included grade 1-2 diarrhea (83%), vision disorders (50%), fatigue (50%), and constipation (33%). The only treatment-related grade 3 AE was alkaline phosphatase elevation in 1 patient. The study was closed due to poor accrual in December 2012. Table 1Patient Best Response RECIST v1.1. Progression-Free Survival (months) 1 -4.9% 2.80 2 36.5 0.73 3 5.1 1.03* 4 121.9 1.43 5 11 2.60 6 69.5 1.30 * Censored (Discontinued due to toxicity)
Conclusion:
Although limited by a small sample size and premature closure, this study suggests that AUY922 is associated with minimal anti-tumor activity in ALK-positive patients previously treated with ALK inhibitors. Combinations of ALK TKIs and HSP90 inhibitors may represent an alternative strategy, and several such studies are now ongoing.
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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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P3.04-027 - Targeted next Generation Sequencing in Lung Cancer: Genomic Oncology in Daily Practice (ID 103)
09:30 - 09:30 | Author(s): D.B. Costa
- Abstract
Background:
Tumor genotyping using single gene assays (SGAs) is a standard approach in the management of advanced NSCLC. We evaluated how therapeutic decision-making was altered by the introduction of next generation sequencing (NGS) into routine clinical practice.
Methods:
Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution.
Results:
82 tumors were genotyped: 75 by SGAs, 7 by NGS alone, and 22 by SGAs and NGS. SGAs identified 10 EGFR-mutated, 3 ALK-rearranged, and 21 KRAS-mutated tumors. Sequential testing with SGAs followed by NGS was more common for patients with EGFR/ALK/KRAS-negative tumors (22/29 or 75.9%) and adenocarcinomas (ACs) (21/22 or 95.5%). Most EGFR/ALK/KRAS-negative tumors were sent for NGS (21/35 or 60%). Of 17 ACs, 10 harbored abnormalities in a known driver oncogene (1-EGFR, 2-ERBB2, 1-ROS1, 1-RET, 2-MET, 2-KRAS and 1-MAP2K1). Primary NGS was used mainly in squamous cell cancers (SCCAs) (6/7 or 85.7%). In 7 SCCAs, 1 sample had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). NGS was successful in 24/29 (82.7%) tumors overall. There was a trend toward increased assay failure in those samples undergoing sequential SGAs followed by NGS as compared to primary NGS alone. All patients with EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. Clinical decisions were impacted by NGS results in 8/17 (47.0%) ACs (trial consideration in 6, off-label TKI use in 2). Therapeutic decisions were influenced by NGS results in 0/7 SCCAs (p=0.0538 when compared to ACs). Actionable therapeutic targets were significantly more frequent in patients with a ≤15 pack-year tobacco history vs. those with >15 pack-years of tobacco use (17/27 or 62.9% vs. 3/42 or 7.1%, respectively; p<0.0001). Only 1/9 (11%) of oncologists demonstrated a detailed understanding of the genomic technologies being used. Figure 1
Conclusion:
Targeted NGS can identify a significant number of driver events in lung ACs—particularly in never/light smokers—for which targeted therapies are available or in development. However, for SCCAs, NGS results are less likely to alter standard practice, barring participation in biomarker-driven studies. Future research into the cost effectiveness and optimal use of NGS in NSCLC is warranted, as well as continued efforts to improve provider awareness and application of genomic technologies.
