SUPPLEMENTAL APPENDIX

SUPPLEMENTAL METHODS

Study design and treatment In each dosing cohort, three patients were enrolled sequentially. If one patient experienced a dose-limiting toxicity (DLT) in the first cycle, the cohort was expanded to six patients. The dose was escalated to the next level provided that fewer than two patients experienced a DLT during the first cycle. If two of three or two of six patients at a given dose level presented with a DLT during the first cycle, this level was to be considered the maximally administered dose. The dose was then to be de-escalated to a previous lower level and expanded to a minimum of six patients until the maximum tolerated dose was reached. DLTs were defined as grade ≥4 hematologic adverse events (AEs) or grade ≥3 non-hematologic AEs that occurred in cycle 1 of treatment in the escalation phase and could be attributed to dacomitinib or crizotinib without a clear alternative explanation and despite medical intervention.

PK Only PK parameters from patients who received the prescribed dose at steady state were included in the PK results. Among these, only patients with area under the plasma concentration−time curve at 10 or 24 hours data

(AUC10 for crizotinib or AUC24 for dacomitinib) on both day −1 and cycle 2 day 1 were considered evaluable for statistical analysis of PK drug interactions. SUPPLEMENTAL FIGURE 1. Study Design.

aPatients enrolled either with no prior dacomitinib therapy or after progression on dacomitinib in another ongoing dacomitinib clinical trial. BID, twice daily; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; PK, pharmacokinetics; QD, once daily; RP2D, recommended phase II dose; TKI, tyrosine kinase inhibitor. SUPPLEMENTAL TABLE 1. Dose-escalation and Reduction Schedules as Per Protocol, for the Dose-escalation Phase As shown in Supplemental Figure 1, only dose levels –1 to 3 were used.

Dose Levels Crizotinib Dacomitinib 200 mg QD 30 mg QD –5 200 mg QD 45 mg QD –4 250 mg QD 15 mg QD –3 250 mg QD 30 mg QD –2 250 mg QD 45 mg QD –1 1 200 mg BID 30 mg QD 2 250 mg BID 30 mg QD 3 200 mg BID 45 mg QD 4 250 mg BID 45 mg QD BID, twice daily; QD, once daily. SUPPLEMENTAL TABLE 2. Progression-free Survival (Safety Analysis Population)

Escalation Expansio Expansio Expansio Overall Cohort n Cohort n Cohort n Total Total (n = 33) 1 2 (n = 35) (n = 68) (n = 23)a (n = 12) Number with event, n 25 (76) 16 (70) 10 (83) 26 (74) 51 (75) (%) Probability of being event-free,b % (95% CIc) Month 2 71.5 53.8 55.0 54.3 63.0 (51.0– (28.4,73.7 (23.2– (34.6– (49.1– 84.6) ) 78.3) 70.5) 74.1) Month 4 37.6 28.7 36.7 31.9 34.5 (20.0– (9.8–51.1) (11.3– (15.7– (22.2– 55.2) 63.0) 49.4) 47.1) Month 6 13.6 7.2 18.3 10.0 11.8 (3.7–29.8) (0.5–27.3) (2.9–44.4) (1.9–26.1) (4.6–22.6) Median,b months (95% 3.0 2.1 2.1 2.1 3.0 CId) (2.8–4.3) (1.4–4.4) (1.4–5.3) (1.4–3.5) (1.8–3.5) aTwo patients with a missing first dose date during the combination dosing period were excluded from the analysis. bEstimated using the Kaplan-Meier method. cCalculated using the normal approximation of the log-transformed cumulative hazard rate. dCalculated using the Brookmeyer-Crowley method. CI, confidence interval. SUPPLEMENTAL TABLE 3. Best Overall Response, Tumor Genotype, and Tumor EGFR and MET Expression in Individual Patientsa in the Expansion Cohorts

Tumor Genotype IHC Analysis EGFR EGFR MET Patient BOR Exon 18 Exon 19 Exon 20 Exon 21 KRA H-score 3+ (%) 2+/3+ (%) H-score 3+ (%)b 2+/3+ (%) S 1 SD WT Del T790M WT WT 240 65 85 285 88 98 2 PD WT Del T790M WT WT 288 93 96 228 33 95 3 Ind WT Del T790M WT WT 260 80 85 115 25 40 4 Ind G719X WT T790M/S768I WT WT 280 80 100 125 10 25 5 SD WT WT T790M L858R WT 228 30 98 200 5 95 6 PR WT Del T790M WT WT 284 87 97 140 5 40 7 PD WT Del T790M WT WT na na na 70 0 5 8 Ind WT Del T790M WT WT 146 16 40 24 0 2 9 PD WT WT T790M L858R WT 155 20 55 2 0 0 10 PD WT Del T790M WT WT na na na na na na 11 PD WT WT WT L858R WT 160 30 35 290 90 100 12 Ind WT WT WT WT G12C na na na 280 85 95 13 PD WT WT WT L858R WT 110 10 25 218 35 85 14 Ind WT Del WT WT WT na na na 100 15 25 15 Ind WT WT WT L858R WT 17 0 7 54 3 6 16 SD G719X WT S768I WT WT 82 0 2 99 0 2 17 SD WT WT WT L858R WT 7 0 2 95 0 15 18 Ind WT Del WT WT WT na na na 55 0 5 19 SD WT WT WT L858R OOD na na na 24 0 8 R 20 Ind WT WT WT WT WT 25 0 5 20 0 5 21 Ind QNS QNS QNS QNS QNS 300 100 100 300 100 100 22 PD QNS QNS QNS QNS QNS na na na 299 99 100 23 PD QNS QNS QNS QNS QNS na na na 297 98 99

Page 5 of 6 Tumor Genotype IHC Analysis EGFR EGFR MET Patient BOR Exon 18 Exon 19 Exon 20 Exon 21 KRA H-score 3+ (%) 2+/3+ (%) H-score 3+ (%)b 2+/3+ (%) S 24 SD QNS QNS QNS QNS QNS 95 25 30 295 95 100 25c PD QNS QNS QNS QNS QNS na na na 295 95 100 26 PD QNS QNS QNS QNS QNS 275 75 100 283 90 94 27 PD QNS QNS QNS QNS QNS 300 100 100 287 85 93 28 PD QNS QNS QNS QNS QNS 226 51 82 43 5 5 29 SD QNS QNS QNS QNS QNS 100 0 30 135 2 48 30 Ind QNS QNS QNS QNS QNS 291 95 98 165 0 75 31 SD QNS QNS QNS QNS QNS 2 0 0 0 0 0 32 SD QNS QNS QNS QNS QNS na na na na na na 33 PD NTI NTI NTI NTI NTI na na na na na na 34 PD NTI NTI NTI NTI NTI na na na na na na 35 SD NTI NTI NTI NTI NTI na na na na na na aPatients with tumor samples; arranged based on 1) EGFR exon 20 genotype and 2) percent 3+ MET expression. bBased on Wu et al.43 cPatient with low-level MET amplification. BOR, best overall response; Del, deletion; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; Ind, indeterminate; na, not available; NTI, no tumor identified; OODR, out of detectable range; PD, progressive disease; PR, partial response; QNS, quantity not sufficient; SD, stable disease; WT, wild-type.

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