Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the Phase III LUX-Lung 8 trial

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1 Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the Phase III LUX-Lung 8 trial lenwood oss, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Alessandro Morabito, Istvan Albert, abriella Herodek, Samuel Chan, yula Ostoros, Veronika Sarosi, Zsolt Kiraly, Deric Savior, Rachael Barton, Francisco Medina, Sundaram Subramanian, Andrea Ardizzoni, Enriqueta Felip, Shirish M. adgeel, Vassilis eorgoulias, Nicholas Dupuis, James Love, Claudia Bühnemann, Neil ibson, Eva Ehrnrooth, Jean-Charles Soria Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the phase III LUX-Lung 8 trial lenwood oss

2 Disclosure information Dr oss reports advisory board participation for and honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Pfizer Acknowledgements We thank all patients and their families, and investigators and staff at all clinical sites for their valuable participation in this study Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Hannah Detering of eomed, an Ashfield company, part of UD Healthcare plc, during the development of this oral presentation Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the phase III LUX-Lung 8 trial lenwood oss

3 Introduction Overexpression/aberrations of ErbB family members (EFR, ErbB2, ErbB4) are implicated in the pathogenesis of SCC of the lung, providing rationale for therapeutic targeting 1-5 The LUX-Lung 8 study compared the irreversible ErbB family blocker, afatinib, with the reversible EFR TKI, erlotinib, in patients with SCC of the lung who had progressed after 4 cycles of platinum-doublet chemotherapy 6 Afatinib significantly improved PFS and OS versus erlotinib in this setting 6 PFS: 2.6 months vs 1.9 months; HR=0.81 (95% CI: ) OS: 7.9 months vs 6.8 months; HR=0.81 (95% CI: ) Afatinib is approved for the treatment of metastatic SCC of the lung following progression after platinum-based chemotherapy Presentation Number: Second-line afatinib for advanced squamous 1. Lawrence cell carcinoma MS, et al. Nature of the 2013;499:214 8; lung: analysis 2. Hirsch of afatinib FR, et al. long-term J Clin Oncolresponders 2003;21: ; OS, overall survival; PFS, progression-free survival; in the phase III LUX-Lung 8 trial IASLC 17 th 3. Heinmoller P, et al. Clin Cancer Res 2003;9: ; 4. Ugocsai K, et al. Anticancer Res 2005;25:3061 6; WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria SCC, squamous cell carcinoma; TKI, tyrosine-kinase inhibitor; 5. Lopez-Malpartida AV, et al. Lung Cancer 2009; 65:25 33; 6. Soria J-C, et al. Lancet Oncol 2015;16:

4 LUX-Lung 8: Study design SCC of the lung (Stage IIIB/IV) Progressed after 4 cycles of a first-line platinum-doublet chemotherapy ECO PS 0 1 Adequate organ function Afatinib 40 mg* qd (n=398) 1:1 Stratified by east Asian vs non-east Asian Erlotinib 150 mg qd (n=397) Primary endpoint: PFS by independent review Key secondary endpoint: OS Other secondary endpoints: ORR, DCR, tumour shrinkage, PRO, safety *Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted; in the phase III LUX-Lung 8 trial IASLC 17 th WORLD Dose reduction to 100 or 50 mg permitted; CONFERENCE ON LUN Tumour assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter CANCER, December 4 7, 2016 Vienna, Austria DCR, disease control rate; ORR, objective response rate; PRO, patient-reported outcomes; qd, once daily

5 Post-hoc analysis of LUX-Lung 8 Long-term responders (LTRs) OS: primary analysis 12 and 18-month OS rates indicated that some patients derived prolonged benefit with afatinib Estimated OS probability % 36.4% 14.4% Afatinib (n=398) 22.0% Erlotinib (n=397) Time (months) Post-hoc analysis identified 15 patients (LTRs) who received 12 months of afatinib treatment Median treatment duration was 16.6 months (range: months) Possible molecular/clinical biomarkers indicative of long-term response to afatinib were evaluated Baseline characteristics Efficacy/safety of afatinib Molecular genomic analysis VeriStrat classification* *Serum protein test used to assign a ood or Poor classification, with in the phase III LUX-Lung 8 trial IASLC 17 WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria prognostic and predictive utility for EFR-targeted agents in NSCLC 1 1. regorc V, et al. Lancet Oncol 2014;15(7):713-21

6 Baseline characteristics LTRs treated with afatinib (n=15) All patients treated with afatinib (n=398) Median age, years (range) 65 (54 81) 65 (36 84) Female/male, % 20/80 16/84 Race, % Eastern-Asian 7 22 Non-eastern Asian Never smoker 7 7 Smoking history, % Light ex-smoker* 13 3 Current and other ex-smoker ECO PS, % 0/1 40/60 32/68 Clinical stage, % IIIB/IV 20/80 12/88 Histology, % Best response to first-line chemotherapy, % Squamous Mixed 0 4 CR/PR SD Unknown 0 12 *Less than fifteen pack-years and stopped >1 year before diagnosis; in the phase III LUX-Lung 8 trial IASLC 17 th WORLD <1% were ECO PS 2 due to protocol violations; CONFERENCE ON LUN CANCER, 1% were stage IIIA December 4 7, 2016 Vienna, Austria

7 Treatment response* and OS in LTRs Median OS was 23.1 months (range: months) Median PFS (independent central review) was 16.2 months (range: months) LTRs OS CR PR Duration of response End of treatment Time (months) *Stable disease Presentation unless noted Number: otherwise (patient Second-line 2 was classified afatinib as non-evaluable); for advanced Patients squamous were ordered cell carcinoma and numbered of by the treatment lung: duration, analysis with of patient afatinib 1 being long-term treatment responders longest; First observed response at time of tumour measurement; in the phase III LUX-Lung 8 trial IASLC Last observed 17 th response at time of tumour measurement; WORLD CONFERENCE ON LUN Treatment ongoing until death; CANCER, December 4 7, Received 1 line of chemotherapy after afatinib; 2016 Vienna, Austria CR, complete response; PR, partial response

8 enomic aberrations in LTRs NS was undertaken in 9/15 afatinib-treated LTRs and 132/398 afatinib-treated patients of the overall LUX-Lung 8 population Certain SVs were more common in LTRs than in the overall population tested ErbB and FF family aberrations (SVs or CNAs) Most common aberrations observed in LTRs ( 3 patients) Afatinib LTRs All afatinib-treated ene, % (n=9) (n=132) 100 TP LTRs (n=9) ErbB family LUX-Lung 8 afatinib-treated population (n=132) ErbB2/3/4 22.2/0/ /4.5/ EFR SVs LRP1B MLL MLL KEAP PIK3CA SOX KLHL PIK3CA CNAs *ErbB+ FF+ MAP3K BCL FF *EFR, ErbB2, ErbB3, and ErbB4 genes; in the phase III LUX-Lung FF3, FF4, FF6, FF7, 8 trial IASLC 17 th FF10, FF12, FF14, FF23, FFR1, FFR2, FFR3, and FFR4 genes WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria CNAs, copy number alterations; NS, next generation sequencing; SVs, short variants Proportion of patients with SVs or CNAs (%)

9 VeriStrat status and biomarkers more commonly observed in LTRs 12/14* (86%) LTRs were VS ood compared to 62% in the overall afatinib-treated dataset (n=336) 78% of LTRs with available data had aberrations more common in LTRs than in the overall population LTRs P M P ErbB4; KEAP1 MLL; PIK3CA KEAP1; PIK3CA; ErbB2 MLL MLL; PIK3CA ErbB2 KEAP1; EFR OS VeriStrat ood VeriStrat Poor VeriStrat Missing CR PR Duration of response End of treatment Presentation Number: Second-line afatinib for advanced Time squamous (months) cell carcinoma of the lung: analysis of afatinib long-term responders *VeriStrat data for Patient 8 was not available; in the phase III LUX-Lung 8 Patients were ordered trial IASLC 17 th and numbered by treatment duration, with patient 1 being on treatment longest; WORLD CONFERENCE ON LUN CANCER, December 4 7, First observed response at time of tumour 2016 Vienna, Austria measurement; Last observed response at time of tumour measurement; Treatment ongoing until death P M

10 Subsequent therapies reported for LTRs LTRs* Paclitaxel/carboplatin, gemcitabine Docetaxel Carboplatin/nanoxel Navelbine emcitabine/carboplatin, paclitaxel/carboplatin Docetaxel emcitabine emcitabine Time (months) OS CR PR Duration of response End of treatment *Tumour response was stable disease unless noted otherwise (patient in the phase III LUX-Lung 8 trial IASLC 17 th 2 was classified as non-evaluable); WORLD CONFERENCE ON Patients were ordered and numbered by treatment duration, with patient 1 being on LUN CANCER, December 4 7, 2016 Vienna, Austria treatment longest; First observed response at time of tumour measurement; Last observed response at time of tumour measurement; Treatment ongoing until death

11 Common treatment-related AEs* and tolerability-guided dose adjustments The frequency of common drug-related AEs in LTRs was similar to the overall afatinib-treated population Afatinib 40 mg/day was maintained in 7/15 and escalated to 50 mg in 4/15 LTRs 4/15 dose reduced to 30 or 20 mg; dose reductions did not seem to have a negative impact on OS There were no treatment-discontinuations due to AEs LTRs 50 mg 40 mg 30 mg 20 mg Data unavailable OS Treatment-duration (months) in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria *>20% in overall afatinib-treated population; Patients were ordered and numbered by treatment duration; Treatment ongoing until death

12 Conclusion Afatinib conferred a median survival benefit of nearly 2 years in the LTR subset Small sample size (n=15) limited determination of molecular/clinical markers of LTRs Biomarkers in LTRs versus overall LUX-Lung 8 population: SVs of ErbB2/4, EFR, MLL, PIK3CA and KEAP1 were more frequent in LTRs 86% of LTRs* were VeriStrat-ood (versus 62% in the overall afatinib-treated population) Afatinib-treated patients classified as VeriStrat-ood were nearly four times as likely to survive 12 months as VeriStrat-Poor patients The approved afatinib dose (40 mg/day) was maintained or escalated in 73% of LTRs Reduction to 30 or 20 mg extended treatment in 27%, without discontinuation due to AEs Further studies are required to predict long-term response to afatinib in SCC of the lung *12/14 patients with available VeriStrat data Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the phase III LUX-Lung 8 trial lenwood oss

13 BACK UP Presentation Number OA23.03: Second-line afatinib for advanced squamous cell carcinoma of the lung: analysis of afatinib long-term responders in the phase III LUX-Lung 8 trial lenwood oss

14 Patient disposition in LUX-Lung 8 Assessed for eligibility (n=977) Did not meet entry criteria or did not enter (n=182) Randomised (n=795) Afatinib (n=398) Erlotinib (n=397) 392 treated 395 treated 307 died 325 died 6 still on treatment 3 still on treatment in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria

15 Demographics and baseline characteristics in LUX-Lung 8 Afatinib (n=398) Erlotinib (n=397) Median age (years) Male (%) Race (%) Eastern-Asian Non-eastern Asian Never smoker 7 5 Smoking history (%) Light ex-smoker* 3 3 Current and other ex-smoker ECO (%) 0/1 32/68 34/66 Clinical stage (%) IIIB/IV 12/88 12/87 Histology (%) Squamous Mixed 4 4 Best response to CR/PR first-line SD chemotherapy (%) Unknown *Less than fifteen pack-years and stopped >1 year before diagnosis; Seventy-one (17.8%) and 85 (21.4%) patients were current smokers, respectively;, <1% were ECO PS 2; 1% were stage IIIA; 1% were undifferentiated (considered to be of squamous histology) in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria

16 LUX-Lung 8: Primary endpoint (PFS) Median PFS was significantly longer with afatinib (2.6 months) versus erlotinib (1.9 months; HR=0.81 [95% CI: ]) Estimated PFS probability Afatinib (n=398) Erlotinib (n=397) Median, months HR (95% CI) 0.81 ( ) p value Time (months) Number at risk Afatinib Erlotinib in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria

17 Treatment duration and best response in LTRs Median duration of treatment was 16.6 months (range: months) ORR=33% (n=5) LTRs* Complete response Partial response Stable disease Non-evaluable Treatment duration (months) *Patients were ordered and numbered by treatment duration; in the phase III LUX-Lung 8 trial IASLC Four patients 17 th had stable non-target disease in the absence of baseline-target disease; WORLD CONFERENCE ON LUN CANCER, December 4 7, Classed non-evaluable by the assessing 2016 Vienna, Austria oncologist due to missing baseline CTs

18 enomic aberrations in LTRs and in the overall NS dataset NS was undertaken in 9/15 afatinib-treated LTRs and 245/795 patients of the overall LUX-Lung 8 population Certain SVs were more common in LTRs than in the overall population ErbB and FF family aberrations (SV or CNA) Most common aberrations observed in LTRs ( 3 patients) ene, % Afatinib LTRs (n=9) Overall (n=245) 100 TP LTRs (n=9) ErbB family LUX-Lung 8 population (n=245) ErbB2/3/4 22.2/0/ /6.1/5.7 EFR SVs LRP1B MLL MLL KEAP PIK3CA SOX KLHL PIK3CA CNAs *ErbB+ FF+ MAP3K BCL FF *EFR, ErbB2, ErbB3, and ErbB4 genes; in the phase III LUX-Lung FF3, FF4, FF6, FF7, 8 trial IASLC 17 th FF10, FF12, FF14, FF23, FFR1, FFR2, FFR3, and FFR4 genes WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria NS, next generation sequencing; CNAs, copy number alterations; SVs, short variants Proportion of patients with SVs or CNAs (%)

19 Details of subsequent therapy Patient number Line of therapy Additional cancer therapy Start date, days after last afatinib dose Stop date, days after last afatinib dose First compound* Second compound* Third compound* Paclitaxel Carboplatin emcitabine Docetaxel Carboplatin Nanoxel Navelbine emcitabine Carboplatin emcitabine Paclitaxel Carboplatin Docetaxel emcitabine emcitabine in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria *Dictionary term

20 Common treatment-related AEs*: Incidence and onset The frequency of drug-related AEs in LTRs was similar to the overall afatinib-treated population AEs generally occurred soon after treatment onset Related AEs in LTRs All grades, n (%) rade 3, n (%) Median AE onset, days (range) Diarrhoea 11 (73) 1 (7) 11 (5 48) Rash/acne 11 (73) 1 (7) 17 (9 107) Stomatitis 2 (13) 1 (7) 98 (11 223) *>20% in overall afatinib-treated population; rouped term in the phase III LUX-Lung 8 trial IASLC 17 th WORLD CONFERENCE ON LUN CANCER, December 4 7, 2016 Vienna, Austria