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Shirish M Gadgeel
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.27 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 10923)
11:30 - 11:30 | Author(s): Shirish M Gadgeel
- Abstract
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.09 - Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC (ID 10759)
16:35 - 16:40 | Author(s): Shirish M Gadgeel
- Abstract
- Presentation
Background:
Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.
Method:
Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).
Result:
753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups PFS, HR (95% CI) OS, HR (95% CI) OAK primary population (N = 850)[a] ITT[a] 0.95 (0.82, 1.10) 0.73 (0.62, 0.87) TC1/2/3 or IC1/2/3[a ](n = 463) 0.91 (0.74, 1.12) 0.74 (0.58, 0.93) TC2/3 or IC2/3[a] (n = 265) 0.76 (0.58, 0.99) 0.67 (0.49, 0.90) OAK BEP for Teff GE (N = 753) BEP 0.94 (0.81, 1.10) 0.71 (0.59, 0.85) TC1/2/3 or IC1/2/3 (n = 420) 0.93 (0.76, 1.15) 0.74 (0.58, 0.95) Teff GE subgroups ≥ 25% (n = 570) 0.91 (0.76, 1.09) 0.67 (0.54, 0.83) < 25% (n = 183) 1.11 (0.82, 1.49) 0.87 (0.63, 1.21) ≥ 50% (n = 379) 0.73 (0.58, 0.91) 0.59 (0.46, 0.76) < 50% (n = 374) 1.30 (1.05, 1.61) 0.87 (0.68, 1.11) ≥ 75% (n = 190) 0.66 (0.48, 0.91) 0.60 (0.42, 0.87) < 75% (n = 563) 1.10 (0.92, 1.31) 0.76 (0.62, 0.92) [a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.
Conclusion:
This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 15:50 | Author(s): Shirish M Gadgeel
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.03 - 3-Year Survival and Duration of Response in Randomized Phase II Study of Atezolizumab vs Docetaxel in 2L/3L NSCLC (POPLAR) (ID 8703)
11:10 - 11:15 | Author(s): Shirish M Gadgeel
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) has demonstrated OS benefit over docetaxel in a randomized Phase II study, POPLAR, in patients with advanced NSCLC. This benefit has been confirmed in the randomized Phase III study OAK (Rittmeyer, 2017). The 3-year survival analysis of the POPLAR study presented here describes the longest survival follow-up reported to date of an all-comer randomized PD-L1/PD-1 immunotherapy trial in 2L+ NSCLC.
Method:
Patients were randomized 1:1 to receive atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. Tumors were prospectively evaluated for tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression using the VENTANA SP142 IHC assay. Landmark OS was estimated using the Kaplan-Meier method. Data cutoff, April 7, 2017; minimum follow-up, 3 years.
Result:
The 2-year and 3-year survival with atezolizumab vs docetaxel were 32.2% vs 16.6% and 18.7% vs 10.0%, respectively. The long-term OS benefit of atezolizumab vs docetaxel was observed across histology and PD-L1 expression subgroups (Table). While the TC3 or IC3 subgroup derived the greatest OS benefit, the TC0 and IC0 subgroup also had improved long-term OS with atezolizumab vs docetaxel. The ITT ORR was 15% in both atezolizumab and docetaxel arms, but the median duration of response was 3 times longer with atezolizumab (22.3 months [95% CI: 11.6, 31.1] vs 7.2 months [95% CI: 5.8, 12.2] with docetaxel). Seven of the 11 docetaxel-arm 3-year survivors received subsequent non-protocol therapy with anti–PD-L1/PD-1 agents. Atezolizumab had a favorable safety profile compared with docetaxel that was consistent with previous reports.
Conclusion:
Atezolizumab demonstrates superior 2-year and 3-year OS benefit compared with docetaxel, and this benefit is observed across histology and PD-L1 expression subgroups (including TC0 and IC0). Atezolizumab is well tolerated, and responses are highly durable. These results are consistent with long-term OS results from OAK, presented separately.Table. Landmark OS in the ITT, PD-L1 expression, and histology subgroups in POPLAR Population (n, atezolizumab vs docetaxel) 2-year OS rate, % 3-year OS rate, % Atezolizumab Docetaxel P value[a] Atezolizumab Docetaxel P value[a] ITT (144 vs 143) 32.2% 16.6% 0.0027 18.7% 10.0% 0.0419 PD-L1 Expression Subgroups TC3 or IC3 (24 vs 23) 41.7% 19.9% 0.1003 37.5% 14.9% 0.0724 TC2/3 or IC2/3 (50 vs 55) 36.1% 13.8% 0.0082 21.2% 9.9% 0.1166 TC1/2/3 or IC1/2/3 (93 vs 102) 36.0% 19.8% 0.0124 18.0% 11.0% 0.1759 TC0 and IC0 (51 vs 41) 25.0% 6.8% 0.0202 20.5% 6.8% 0.0693 Histology Subgroups Non-squamous (95 vs 95) 32.2% 21.1% 0.0960 23.3% 12.4% 0.0585 Squamous (49 vs 48) 32.7% 7.8% 0.0020 9.4% 5.2% 0.4603 [a ]For descriptive purpose only. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC2/3 or IC2/3 = PD-L1 ≥ 5% TC or IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT01903993.
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MTE 13 - Malignant Pleural Mesothelioma: State of the Art (Sign Up Required) (ID 562)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 07:00 - 08:00, Room 501
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MTE 13.02 - Systemic Treatments for Malignant Pleural Mesothelioma (ID 7793)
07:30 - 08:00 | Presenting Author(s): Shirish M Gadgeel
- Abstract
- Presentation
Abstract not provided
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update (ID 9059)
14:30 - 14:40 | Author(s): Shirish M Gadgeel
- Abstract
- Presentation
Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.
Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).
Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.
Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-011 - Development of Novel Blood-Based Biomarker Assays in 1L Advanced/ Metastatic NSCLC: Blood First Assay Screening Trial (BFAST) (ID 8398)
09:30 - 09:30 | Author(s): Shirish M Gadgeel
- Abstract
Background:
Worldwide it is estimated that 20%-30% of advanced NSCLC patients do not receive a complete molecular diagnosis at baseline and are ineligible for targeted therapies due to tissue biopsy limitations. Blood-based, multiplex testing that analyzes circulating tumor DNA (ctDNA) by targeted next-generation sequencing offers a minimally invasive testing method, but clinical utility has yet to be established. High tumor mutational burden (TMB) measured in tissue is associated with atezolizumab (anti–PD-L1) clinical activity in several tumor types, including NSCLC. Alectinib, a potent, selective ALK/RET kinase inhibitor, has shown activity in 1L and is approved as 2L therapy in patients with ALK- or RET-positive advanced NSCLC but requires tissue for analysis. Here we present an umbrella trial that aims to clinically validate novel blood-based diagnostic assays that measure TMB in the blood (bTMB) and somatic mutations (e.g., ALK/RET), and to determine the efficacy and safety of 1L atezolizumab or alectinib in biomarker-selected NSCLC patients.
Method:
BFAST is a Phase II/III global, multicenter, open-label, multi-cohort screening and interventional umbrella trial designed to evaluate the safety and efficacy of targeted therapies in patients with unresectable, advanced or metastatic NSCLC selected based on the presence of oncogenic somatic mutations or a positive bTMB score. Key eligibility criteria include previously untreated, stage IIIB-IVB NSCLC of any histology and measurable disease per RECIST v1.1. Pre-enrollment blood-based screening will identify patients whose tumors harbor oncogenic somatic mutations (ALK/RET) or a positive bTMB score (above a pre-specified cutoff); patients will be assigned to the appropriate cohort based on the screening results. Study treatment will continue until disease progression (all cohorts) or loss of clinical benefit (atezolizumab only) (Table). The modular trial design allows for additional biomarker-driven BFAST cohorts with distinct screening and treatment requirements, and endpoints such as ORR with highly active drugs.Table. BFAST Study Details Cohort Treatment Planned Enrollment, n Primary Endpoints Key Secondary Endpoints Cohort AALK+ Alectinib 600 mg PO bid 78 ORR per RECIST v1.1 (INV-assessed) DOR, CBR[c] and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS Cohort B RET+ Alectinib 900 and 1200 mg dose escalation 52-62 ORR per RECIST v1.1 (INV-assessed) DOR, CBR and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS Cohort C bTMB+ Atezolizumab 1200 mg IV q3w or platinum-based chemotherapy[a] ≈440 (R, 1:1)[b] PFS per RECIST v1.1 (INV-assessed) OS PFS, ORR and DOR per RECIST v1.1 (IRF-assessed) ORR and DOR per RECIST v1.1 (INV-assessed) 6- and 12-month PFS rates [a ]Cisplatin or carboplatin + pemetrexed for non-squamous histology, and cisplatin or carboplatin + gemcitabine for squamous histology. Administered per standard of care. [b ]Stratification factors include tissue availability, ECOG performance status, bTMB level and tumor histology. [c ]CBR is defined as the rate of patients with confirmed CR or PR or stable disease that has been maintained for ≥ 24 weeks. bid, twice a day; bTMB, blood tumor mutational burden; CBR, clinical benefit rate; INV, investigator; IRF, independent review facility; IV, intravenously; PO, orally; q3w, every 3 weeks; R, randomized.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-043 - Impact of ErbB Mutations on Clinical Outcomes in Afatinib- or Erlotinib-Treated Patients with SCC of the Lung (ID 9457)
09:30 - 09:30 | Presenting Author(s): Shirish M Gadgeel
- Abstract
Background:
In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations.
Method:
Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression.
Result:
Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients, PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188).
Conclusion:
These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action.Subgroup n Afatinib vs erlotinib PFS OS HR (95% CI) p~interaction~ HR (95% CI) p~interaction~ ErbB mutation-positive ErbB mutation-negative 53 192 0.56 (0.29–1.08) 0.70 (0.50–0.97) 0.718 0.62 (0.35‒1.12) 0.76 (0.56‒1.03) 0.683 EGFR mutation-positive EGFR mutation-negative 16 229 0.64 (0.17–2.44) 0.67 (0.50–0.91) 0.981 1.01 (0.32–3.16) 0.72 (0.54–0.95) 0.529 HER2 mutation-positive HER2 mutation-negative 12 233 0.06 (0.01–0.59) 0.72 (0.54–0.97) 0.006 0.06 (0.01–0.57) 0.76 (0.58–1.00) 0.004 HER3 mutation-positive HER3 mutation-negative 15 230 0.52 (0.16–1.72) 0.69 (0.51–0.94) 0.692 0.84 (0.27–2.59) 0.73 (0.56–0.97) 0.998 HER4 mutation-positive HER4 mutation-negative 14 231 0.21 (0.02–1.94) 0.67 (0.50–0.91) 0.909 0.22 (0.05–1.04) 0.75 (0.56–0.99) 0.272 EGFR IHC positive EGFR IHC negative 292 53 0.74 (0.56–0.97) 0.76 (0.41–1.40) 0.985 0.82 (0.63–1.06) 0.75 (0.41–1.40) 0.882 EGFR amplification present EGFR amplification absent 17 228 0.72 (0.18–2.90) 0.68 (0.50–0.92) 0.994 0.50 (0.15–1.65) 0.76 (0.58–1.00) 0.413 HER2 amplification present HER2 amplification absent 9 236 0.94 (0.20–4.38) 0.68 (0.50–0.91) 0.861 1.10 (0.27–4.48) 0.72 (0.54–0.94) 0.388
