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C.S. Sima
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MINI 06 - Quality/Prognosis/Survival (ID 111)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 2
- Moderators:R. Meguid, J. Yoshida
- Coordinates: 9/07/2015, 16:45 - 18:15, 605+607
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MINI06.02 - T1a Lung Adenocarcinomas: Presence of Spread of Tumor through Alveolar Spaces (STAS), Micropapillary and Solid Patterns Determines Outcomes (ID 3068)
16:50 - 16:55 | Author(s): C.S. Sima
- Abstract
- Presentation
Background:
Our previous reports highlighting the significance of presence of micropapillary (MIP) (JNCI 2013), STAS- spread of tumor through alveolar spaces (JTO 2015), and predominant solid (SOL) (Modern Pathol 2011) histological subtype as poor prognostic markers in stage I lung adenocarcinomas (ADC) are reproduced by others. In this study, we hypothesized that presence of STAS, MIP or SOL patterns (≥5%) in small stage I lung ADC (≤2 cm) is a marker of invasion and poor prognosis, and can influence the recurrence patterns based on the type of surgical resection – lobectomy (LO) versus limited resection (LR).
Methods:
All available tumor slides from patients with therapy-naive, surgically resected small (≤ 2cm), solitary stage I lung ADC were reviewed (1995-2011; n = 909). STAS was defined as isolated tumor cells within alveolar spaces separate from the main tumor. MIP and SOL patterns were considered present in the tumor when it comprised ≥5% of the overall tumor. Cumulative incidence of recurrence (CIR; any types, locoregional or distant) was estimated using a cumulative incidence function. Differences in CIR between groups were assessed using Gray’s method.
Results:
Figure 1 The association of outcomes with the presence of STAS, MIP, or SOL patterns is shown in the table. The risk of developing any types of recurrence was significantly higher in patients with both STAS and MIP positive tumors than others (P < 0.001); and the risk of developing any types of recurrence was significantly lower in patients with both STAS and SOL negative tumors than others (P < 0.001). In the LR group, STAS, MIP and SOL patterns were independent prognostic factors for any types of recurrence (HR: 4.5, 1.4, and 1.3, respectively), locoregional recurrence (HR: 5.2, 1.3, and 1.3, respectively), and distant recurrence (HR: 3.1, 1.4, and 1.2, respectively).
Conclusion:
Tumor STAS, presence of MIP and SOL patterns are independent risk factors of recurrence especially in the LR group of small stage I lung ADC patients. Importantly, of these factors, tumor STAS was the strongest predictor of locoregional recurrence in this group. These results suggest that the identification of STAS in small lung ADC may identify LR patients who need further management, one of which may be completion lobectomy.
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MINI06.13 - Multiple Lung Cancers: Is Their Survival Better or Worse Then Other Lung Cancers? (ID 3058)
17:55 - 18:00 | Author(s): C.S. Sima
- Abstract
- Presentation
Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The prognosis of MLCs is not known. Herein, we evaluate the prognosis of patients with MLCs, one resected LC, and recurrent LC, to ascertain whether patients with MLCs have a distinct natural history compared to the other two groups.
Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria and comprehensive pathologic assessment. Clinicopathologic data was collected. We used the Kaplan-Meier method and log-rank test to assess overall survival (OS) of patients with MLCs, one LC, or recurrent LC, from the time of surgery/pathologic confirmation of their MLC, one LC, or recurrent LC, respectively.
Results:
2352 patients were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113).Median OS and 2-year OS for patients in these subgroups stratified by stage, is depicted in Table 1. In patients with one LC, never smokers (p<0.001), adenocarcinoma histology (p<0.001), and surgery type (p<0.001) were associated with improved OS. In patients with recurrent LC, never smokers (p=0.015), and adenocarcinoma histology (p=0.009) were associated with favorable OS, compared to smokers and squamous histology respectively. In patients with MLCs, adenocarcinoma histology was associated with improved OS when compared to squamous histology (p=0.049).Pathologic Stage (n) Median Overall Survival (months, 95% CI) Two-Year Overall Survival p value One Lung Cancer (n=2238) All Not Reached (75.2-NA) 0<0.001 IA 0.914 IB 0.841 IIA 0.789 IIB 0.755 IIIA 0.691 Multiple Lung Cancers(n=113) All 55.5 (49.4-NA) 0.32 IA 0.810 IB 0.806 II/III 0.830 Recurrent Lung Cancer (n=348) All 10.4 (9.1-12.3) 0.077 IA 0.263 IB 0.180 IIA 0.273 IIB 0.351 IIA 0.083
Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessments successfully identify patients with MLCs. Prognostic data for patients with MLCs, one LC and recurrent LC, highlight that these patients have a long natural history. MLCs have a long survival stage for stage, which underscores a definitive therapeutic approach where possible, based on favorable prognosis of these patients.
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.14 - A Phase 1 Study of Erlotinib and Ruxolitinib in Patients with EGFR-Mutant Lung Cancers and Acquired Resistance to Erlotinib Therapy (ID 2818)
18:00 - 18:05 | Author(s): C.S. Sima
- Abstract
- Presentation
Background:
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, often associated with acquisition of EGFR T790M. Upregulation of JAK/STAT signaling is involved in resistance to EGFR TKIs and JAK inhibition is a proposed treatment strategy in the setting of acquired resistance by restoring sensitivity to erlotinib. Ruxolitinib is an FDA-approved oral JAK1/2 inhibitor given at 20mg twice daily for hematologic malignancies with a largely non-overlapping toxicity profile with erlotinib.
Methods:
We evaluated the toxicity and efficacy of once daily oral erlotinib and twice daily oral ruxolitinib in patients with EGFR-mutant lung cancers and acquired resistance to erlotinib therapy (NCT02155465). Using a 3+3 dose escalation, we assessed escalating doses of ruxolitinib (10mg BID, 15mg BID, 20mg BID) with erlotinib 150mg daily for 21 day cycles. Response was evaluated by RECIST 1.1. Tissue and peripheral blood samples were obtained; exosomes will be extracted from peripheral blood and molecular and proteomic analyses will be performed.
Results:
From May 2014 to February 2015, 12 patients (pts) were enrolled. Median age: 60; Women: 7 (58%); never-smokers: 6 (50%); EGFR L858R=4 (33%) and Exon 19 deletion=8 (67%). Two of twelve (17%) were EGFR T790M positive at rebiopsy at the time of acquired resistance. Of 12 pts treated, 3 received ruxolitinib 10mg BID, 3 received 15mg bid and 6 received 20mg BID with erlotinib 150mg daily. No dose limiting toxicities were seen. The recommended phase 2 dose is ruxolitinib 20mg BID with 150mg erlotinib daily. Treatment-related AEs were all grade 1-3. The most frequent treatment related clinical adverse events (all grade 1-3) were anemia (25%), diarrhea (25%), rash (25%), pain (17%), fatigue (8%), and pneumonitis (8%). The most frequent treatment-related laboratory adverse events (all grade 1-2) were anemia (33%), elevated ALT (17%), elevated AST (17%), and hyperbilirubinemia (8%). Of the 12 pts treated, 2 (17%) required a dose reduction of erlotinib for treatment emergent toxicities; both subjects were on lower doses of erlotinib than 150mg daily prior to study enrollment. There were no dose reductions of ruxolitinib. Of 12 evaluable patients, no partial responses were seen. The median-progression free survival is 3 months. Two patients remain on study. One patient has been on study for 10 months with ongoing stable disease. Nine patients (75%) came off study for progression, 1 (8%) for toxicity. One person discontinued treatment on study for grade 3 pneumonitis, possibly related to the combination of erlotinib and ruxolitinib. The symptoms resolved with discontinuation of erlotinib and ruxolitinib.
Conclusion:
Combination erlotinib and ruxolitinib is well-tolerated. The phase 2 dose of ruxolitinib is 20mg BID in combination with erlotinib. There were no partial responses, but durable disease control was seen in some patients. The phase 2 study of erlotinib and ruxolitinib in this population is ongoing.
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ORAL 03 - New Kinase Targets (ID 89)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:F. Blackhall, R. Juergens
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL03.05 - Clinical Outcomes with Pemetrexed-Based Systemic Therapy in RET-Rearranged Lung Cancers (ID 2813)
11:28 - 11:39 | Author(s): C.S. Sima
- Abstract
- Presentation
Background:
Previous series have shown that clinical benefit with pemetrexed-based systemic therapy can be durable in patients with ALK- and ROS1-rearranged lung cancers. The benefit of pemetrexed-based treatment in RET-rearranged lung cancers relative to other genomic subsets has not been explored.
Methods:
A retrospective review of records of patients treated at Memorial Sloan Kettering between 2007-2014 was conducted. Eligibility criteria: pathologically-confirmed advanced (stage IIIB/IV) non-small cell lung carcinoma, treatment with pemetrexed as monotherapy or in combination with other systemic agents, documented evidence of a rearrangement involving RET, ROS1, or ALK, or a KRAS mutation. Screening for these alterations was performed via break apart fluorescence in situ hybridization, multiplex mutation hotspot testing (Sequenom), or next-generation sequencing (MSK-IMPACT, Illumina HiSeq). Progression-free survival (PFS) and time to progression (TTP) were calculated using Kaplan-Meier estimates from the date of initiation of pemetrexed-containing therapy, and overall survival (OS) from diagnosis of metastatic disease. Overall response rate (ORR, RECIST v1.1), PFS, TTP, and OS were compared between RET-rearranged lung cancers and control groups (ALK- and ROS1-rearranged and KRAS-mutant lung cancers).
Results:
Data from 104 patients (RET-rearranged n=17, ROS1-rearranged n=10, ALK-rearranged n=36, KRAS-mutant n=41) were evaluated. As expected, median pack-year cigarette smoking history significantly differed between groups (p<0.001): RET 0 (0-48 range), ROS1 0 (0-12), ALK 0 (0-74), KRAS 38 (0-93). Features such as line of pemetrexed therapy (first vs other, p=0.1186), type of therapy (platinum combination, non-platinum combination, vs single-agent, p=0.1435), and need for dose reduction (p=0.9772) did not differ between groups. ORR, TTP, PFS, and OS in RET-rearranged lung cancers were not significantly different compared to ALK- and ROS1-rearranged lung cancers, and improved compared to KRAS-mutant lung cancers (Table 1). Table 1. Clinical Outcomes of Pemetrexed-Based TherapyRET ROS1 ALK KRAS p-value ORR 45% 78% 50% 26% 0.0242 Median TTP (months) NR (20-NR) 32 (14-NR) NR 7 (5-14) <0.001 ALK vs ROS1 vs RET (p=0.90); RET vs KRAS(p=0.009) Median PFS 20 (10-NR) 23 (14-NR) 24 (15-38) 6 (5-9) <0.001 ALK vs ROS1 vs RET (p=0.94); RET vs KRAS(p=0.002) Median OS NR (24-NR) NR (24- NR) 37 (30-63) 16 (13-29) <0.001 ALK vs ROS1 vs RET (p=0.43); RET vs KRAS(p=0.002)
Conclusion:
Clinical benefit with pemetrexed-based therapy in RET-rearranged lung cancers can be durable and is comparable to ALK- and ROS1-rearranged lung cancers. Outcomes in RET-, ROS1-, and ALK-rearranged lung cancers were improved compared to KRAS-mutant lung cancers. Mechanisms responsible for pemetrexed sensitivity in these subsets should continue to be explored. Driver-independent factors such as smoking history may contribute to clinical benefit.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-008 - Diagnostic Molecular Testing in Multiple Lung Cancers (ID 3149)
09:30 - 09:30 | Author(s): C.S. Sima
- Abstract
Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The underlying biology for why MLCs develop is not known. Herein, we evaluate clinicopathologic data for patients with MLCs, and report clonality between MLC lesions using diagnostic molecular testing.
Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases, and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria, and comprehensive pathologic assessment. Clinico-pathologic data was collected for patients with MLCs, including available diagnostic molecular data from sizing assays, Sanger sequencing and mass spectrometry genotyping (Sequenom).
Results:
2352 pts were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113). In patients with MLCs, adenocarcinoma histology (n=97) was associated with improved OS (p=0.049) compared to squamous histology (n=13, other n=3). Paired diagnostic molecular pathology was available in 51 patients with adequate tissue from MLCs. MLC pairs stratified by mutation type are depicted in Table 1. In 49 patients, both MLCs were adenocarcinomas (20= extended panel: sizing assays/Sanger sequencing/Sequenom, 29=limited panel: EGFR/KRAS sizing assay/Sanger sequencing): 51% (n=25/49) had concordant molecular results, suggesting a common tumor clone, and 49% (n=24/49) had discordant results. In 1 patient, one MLC was an adenocarcinoma and the other was a squamous carcinoma, and had discordant molecular results by limited panel testing. In 1 patient, both MLCs were squamous carcinomas, and had concordant molecular results by limited panel testing. In patients where MLCs both had a KRAS mutation (n=11), 3 pairs had the same mutation (KRAS G12C, KRAS G12D, KRAS G12F), and 8 had different mutations. Table 1: Multiple Lung Cancer: Molecular DataFigure 1
Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessment, are currently used to diagnose MLCs. Assuming separate MLC lesions harbor distinct molecularly defined clones, paired molecular testing using limited panels is not sufficient to diagnose MLCs. Concordant molecular profiles do not necessarily define whether a lesion is an MLC or a metastatic lesion. Paired prospective testing of suspected MLC lesions including broader molecular tests such as DNA, RNA, protein expression and immune correlates, may advance our understanding of the biology of these tumors.
