CURRENT STANDARD OF CARE OF LUNG CANCER Maroun El-Khoury, MD Consultant Oncologist/Hematologist American Hospital Dubai President of Medical staff
Biopsy: Establish Diagnosis, Determine Histologic Subtype, Molecular Testing Adequate tissue for histologic subtyping, molecular analysis critical Choice of site to biopsy (avoid bone if possible) Determination of EGFR mutation, ALK, and ROS1 translocations indicated in all nonsquamous cancers Determination of PD-L1 expression indicated in all NSCLC Rebiopsy at time of progression from targeted therapy Helps in determining resistance in EGFR-mutated and ALKpositive cases Liquid biopsy Masters GA, et al. J Clin Oncol. 2015;33:3488-3515. Novello S, et al. Ann Oncol. 2016;27:v1-v27.
Liquid Biopsy Potential Clinical Applications Alix-Panabieres C, Pantel K. Cancer Discov. 2016. Screening and early detection of cancer EGFR mutations in ctdna CTC counts Stratification and therapeutic intervention Real time monitoring of therapy Therapeutic targets and resistance mechanisms Risk for metastatic relapse (prognosis)
Chemotherapy Targeted TKI Therapy Checkpoint Inhibitors Histologic subtype EGFR ALK ROS1 BRAF V600E Anti PD-1 Anti PD-L1 1970s - today 2000s - today 2015 - today How do we optimize therapy in individual pts (ie, first line, second line, third line)?
EGFR Mutations: Context Found in 10% to 30% of NSCLC pts [1] More common in never-smokers, adenocarcinomas, females, Asians [1,2] Predominantly located in EGFR exons 18-21 [2] ~ 85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21 (L858R) [3] Specific EGFR mutation identified is important There are sensitive mutations, primary resistance mutations (often exon 20), and acquired resistance mutations (T790M) [3] 1. Pao W, et al. J Clin Oncol. 2005;23:2556-2568. 2. Wu YL, et al. J Thorac Oncol. 2007;2:430-439. 3. Gazdar AF. Oncogene. 2009;28:S24-S31.
Summary of EGFR Mutation Driven NSCLC EGFR sensitizing mutations predict higher response rate, PFS, and QoL if treated with EGFR TKI first line Several approved EGFR TKIs Specific EGFR mutation is important to know since some predict resistance to EGFR TKIs (eg. exon 20 insertions) Choice of specific EGFR TKI dependent on physician and patient preferences Upon progression, postprogression biopsy is important to establish the mechanism of resistance Liquid biopsy is an option Osimertinib approved for pts with EGFR T790M-positive disease (preferred treatment choice)
Study Treatment N Median PFS, Mos ORR, % Median OS, Mos Maemondo [1] Mitsudomi [2,3 ] OPTIMAL [4,5] EURTAC [6] Gefitinib vs carboplatin/ paclitaxel Gefitinib vs cisplatin/docetaxel Erlotinib vs carboplatin/gemcitabine Erlotinib vs platinum-based chemotherapy LUX-Lung Afatanib vs 3 [7,8] cisplatin/pemetrexed LUX-Lung Afatinib vs 6 [8,9] cisplatin/gemcitabine 230 172 165 173 345 364 10.8 vs 5.4 (P <.001) 9.2 vs 6.3 (P <.0001) 13.1 vs 4.6 (P <.0001) 9.7 vs 5.2 (P <.0001) 11.1 vs 6.9 (P =.001) 11.0 vs 5.6 (P <.0001) 74 vs 31 62 vs 32 83 vs 36 58 vs 15 56 vs 23 67 vs 23 30.5 vs 23.6 (P =.31) 34.8 vs 37.3 (HR: 1.25) 22.8 vs 27.2 (HR: 1.19) 19.3 vs 19.5 (P =.87) 28.2 vs 28.2 (P =.39) 23.1 vs 23.5 (P =.61) 1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Yoshioka H, et al. ASCO 2014. Abstract 8117. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Zhou C, et al. Ann Oncol. 2015;26:1877-1883. 6. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 7. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 8. Yang JC, et al. Lancet Oncol. 2015;16:141-151. 9. Wu YL, et al. Lancet Oncol. 2014;15:213-222.
Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS Study EGFRmut (first-line therapy) EURTAC First-SIGNAL GTOWG INTACT1-2 IPASS LUX LUNG3 NEJ002 OPTIMAL TALENT TOPICAL TRIBUTE WJTOG3405 Subtotal HR (95% CI) 0.37 (0.25-0.54) 0.54 (0.27-1.10) 1.08 (0.24-4.90) 0.55 (0.19-1.60) 0.48 (0.36-0.64) 0.58 (0.43-0.78) 0.32 (0.24-0.44) 0.16 (0.11-0.26) 0.59 (0.21-1.67) 0.90 (0.39-2.06) 0.49 (0.20-1.20) 0.52 (0.38-0.72) 0.43 (0.38-0.49) HR (95% CI) Favors EGFR TKI Favors Chemo Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605.
Estimated OS Probability Estimated OS Probability LUX-Lung 3+6: OS by del(19) and L858R Mutation Status for Afatinib vs Chemo del(19) Afatinib (n = 236) Chemo (n = 119) L858R Afatinib (n = 183) Chemo (n = 93) 1.0 Median, mos 31.7 20.7 HR (95% CI) 0.59 (0.45-0.77) P =.0001 1.0 Median, mos 22.1 26.9 HR (95% CI) 1.25 (0.92-1.71) P =.1600 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 6 12 18 24 30 36 42 48 0 0 6 12 18 24 30 36 42 48 Mos Mos Yang JC, et al. Lancet Oncol. 2015;16:141-151.
Pts (%) LUX-Lung 7: PFS With First-line Afatinib vs Gefitinib in EGFR-Mutated NSCLC PFS significantly longer with afatinib vs gefitinib 100 80 60 Afatinib (n = 160) Gefitinib (n = 159) Median PFS, Mos (95% CI) 11.0 (10.6-12.9) 10.9 (9.1-11.5) 12-Mo PFS *, % (95% CI) 47.4 (39.2-55.2) 41.3 (33.0-49.5) 24-Mo PFS *, % (95% CI) 17.6 (11.7-24.6) 7.6 (3.5-13.8) HR: 0.73 (95% CI: 0.57-0.95; P =.017) *Estimated using exploratory Kaplan-Meier analyses. 40 20 0 0 6 12 18 24 30 36 42 Mos Park K, et al. Lancet Oncol. 2016;17:577-589.
Study or Subgroup T790M Total Percent Chen HJ, et al., 2009 14 29 48% Kosaka T, et al., 2006 7 14 50% Onitsuka T, et al., 2010 7 10 70% Lung CA Oxnard, et al., 2011 58 93 62% Total 86 146 59% Small Cell CA NSCL CA Squamous Cell Lung CA Non Squamous Cell Lung CA (Adeno, large cell) Wild PDL1 50% ALK Rearrangement ROS 1 EGFR mutation Other mutation T790m 50%
Phase I AURA Design AURA Ph I/II Patients with T790M-positive ansclc whose disease has progressed following either one prior therapy with an EGFR-TKI or following treatment with both EGFR-TKI and other anticancer therapy Rolling six design AURA2 Ph II Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI Escalation Cohort 1 20 mg Cohort 2 40 mg Negative Cohort 3 80 mg n=63 Negative Cohort 4 160 mg Cohort 5 240 mg Positive Positive Positive Positive Positive Negative Central T790M mutation testing* of biopsy sample collected following confirmed disease progression Expansion First-line Biopsy Tablet Cytology First-line Biopsy T790M positive T790M negative AURA Phase II Extension (n=201) Osimertinib 80 mg QD Pooled Phase II AURA2 (n=210) Osimertinib 80 mg QD Not eligible for enrollment AURA Ph I data cut-off 4 January, 2016; AURA pooled Ph II data cut-off 1 November, 2015. *The EGFR T790M mutation status of the patient s tumour was prospectively determined by the designated central laboratory using the cobas EGFR Mutation Test (Roche Molecular Systems) by biopsy taken after confirmation of disease progression on the most recent treatment regimen. Paired biopsy cohort patients with T790M positive tumours; safety and efficacy data only reported here. Data from cohorts in grayed out boxes are not included in the analyses reported here. Yang, ELCC 2016
Response Rates of EGFR T790M Positive Cohorts to Osimertinib 50 40 30 20 10 0-10 -20-30 -40-50 -60-70 -80-90 -100 D D*D* D DDD D D DD D DD 20 mg 40 mg 80 mg 160 mg 240 mg D DD D Best % Change From Baseline in Target Lesion D D DD DD DD D D D DD D D D DD DDD D D D D D DD D D DD D D D D D D D D *Imputed values for pts who died within 14 wks (98 days) of start of treatment and had no evaluable target lesion assessments. D Study discontinuation. T790M mutation determined by central test. n = 127 20 mg 40 mg 80 mg 160 mg 240 mg Total n 10 32 61 41 13 157 ORR, % (95% CI) 50 (19-81) DCR (CR, PR, or SD): 90% (95% CI: 84-94); activity in LM Jänne PA, et al. New Engl J Med. 2015;372:1689-1699. Jänne PA, et al. ELCC 2015; Abstract LBA3. Yang, J C-H, et al. ASCO 2016. Abstract 9002. 59 (41-76) 66 (52-77) 51 (35-67) 54 (25-81) 59 (51-66)
Osimertinib in EGFR inhibitor resistant NSCLC RR 61% RR 21% Jänne, NEJM 2015
ALK-Driven Disease All nonsquamous NSCLC should be tested for ALK rearrangements Pts tend to develop brain metastases ALK rearrangements predict higher ORR and PFS if treated with ALK TKI first line Crizotinib and ceritinib are approved Alectinib demonstrated improved PFS and CNS activity over crizotinib as first-line therapy (ALEX) Alectinib, brigatinib, and ceritinib are approved for secondary refractory disease or intolerance to crizotinib Next-generation ALK inhibitors active in CNS disease Many ALK-positive pts may derive benefit from multiple sequential ALK inhibitors
PFS (%) PROFILE 1014: First-line Crizotinib vs Pemetrexed/Platinum* in Advanced NSCLC Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC and no prior systemic treatment for advanced disease 100 80 60 40 Crizotinib Crizotinib (n = 172) Chemotherapy (n = 171) Median PFS, mos 10.9 7.0 HR (95% CI) 0.45 (0.35-0.60) P value <.001 ORR, % 74 45 P value <.001 20 0 Pts at Risk, n Crizotinib CT 0 5 10 15 20 25 30 35 Mos 172 171 Chemotherapy 120 105 65 36 38 12 19 2 7 1 1 0 0 0 *Carboplatin or cisplatin. Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177.
Acquired Resistance in ALK+ NSCLC ALK+ NSCLC is sensitive to crizotinib [1-3 ] ORR: 60% Median PFS: 8-10 mos Most patients with develop resistance to crizotinib [4,5] Usually within 1-2 yrs CNS relapses are common [6] Mechanisms of resistance are diverse [4,5] ALK resistance mutations Alternative signaling pathways Unknown ALK amp ALK+ No ALK amp or mut Bypass tracks EGFR MT KRAS MT ALK mut 1. Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019. 2. Kim DW, et al. ESMO 2012. Abstract 1230PD. 3. Show AT, et al. ESMO 2012. Abstract LBA1_PR. 3. Katayama R, et al. Sci Trans Med. 2012;4:120ra17. 4. Doebele RC, et al. Clin Cancer Res. 2012;18:1472-1482. 5. Takeda M, et al. J Thorac Oncol. 2013; 8:654-657. Used with permission.
TKI Therapy In Pts With ALK+ NSCLC Inhibitors of ALK tyrosine kinase are active in pts with ALK+ NSCLC [1] ALK inhibitor crizotinib preferred therapy for advanced ALK+ NSCLC Phase III PROFILE 1014 study found crizotinib superior to standard first-line pemetrexed + platinum chemotherapy in this setting [2] Crizotinib arm, median PFS: 10.9 mos; ORR: 74% CNS is common initial progression site in ALK+ pts receiving crizotinib [3] Alectinib has demonstrated activity in crizotinib-refractory ALK+ NSCLC [4-6] Current phase III global study designed to compare alectinib vs crizotinib as first-line therapy for advanced ALK+ NSCLC [7] 1. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. 2. Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. 3. Yoshida T, et al. Lung Cancer. 2016;97:43-47. 4. Ou SH, et al. J Clin Oncol. 2016;34:661-668. 5. Shaw AT, et al. Lancet Oncol. 2016;17:234-242. 6. Gadgeel SM, et al. J Clin Oncol. 2016;34:4079-4085. 7. Peters S, et al. N Engl J Med. 2017;[Epub ahead of print].
Second-Generation ALK Inhibitors N Phase Prior Cri? ORR % Median PFS Ceritinib ASCEND-1 [1] ASCEND-2 [2] ASCEND-3 [3] 163 83 140 124 Alectinib Shaw [4] Ou [5] 87 138 I I II II II II Yes No Yes No Yes Yes Brigatinib [6] 222 II Yes Lorlatinib [7] 54 I/II Yes (40/41 pts) 56 72 38.6 63.7 48 50 45 (90 mg QD) 54 (180 mg QD) 6.9 18.4 5.7 11.1 8.1 8.9 15.6 (90 mg QD) NR (180 mg QD) 46 11.4 1. Kim DW, et al. Lancet Oncol. 2016;17:452-63. 2. Mok T, et al. ASCO 2015. Abstract 8059. 3. Felip E, et al. ASCO 2015. Abstract 8060. 4. Shaw AT, et al. Lancet Oncol. 2016;17:234-242. 5. Ou SH, et al. J Clin Oncol. 2016;34:661-668. 6. Kim DW, et al. ASCO 2016. Abstract 9008. 7. Solomon BJ, et al. ASCO 2016. Abstract 9009.
Pts with advanced or metastatic ALK+ NSCLC, no previous systemic therapy for advanced disease, ECOG PS 0-2 (N = 303) Alectinib 600 mg BID PO (n = 152) Crizotinib 250 mg BID PO (n = 151) No crossover allowed Primary endpoint: PFS by investigator review Secondary endpoints: PFS by IRC, time to CNS progression, ORR, DoR, OS, safety Median duration of follow-up at time of analysis, alectinib: 18.6 mos (range: 0.5-29.0 mos); crizotinib: 17.6 mos (range: 0.3-27.0 mos) Peters S, et al. N Engl J Med. 2017;[Epub ahead of print].
PFS (%) 100 80 60 40 20 0 n Crizotinib Alectinib 151 Investigator-Assessed PFS 0 3 6 9 12 15 18 21 24 27 30 132 104 84 11.1 mos Mos 65 46 35 Alectinib Median PFS Investigat orassessed, mos (95% CI) IRCassessed, mos (95% CI) Alectin ib (n = 152) NR (17.7- NR) 25.7 (19.9- NR) 152 135 113 109 97 81 67 35 15 3 Shaw A, et al. ASCO 2017. Abstract LBA9008. Peters S, et al. N Engl J Med. 2017;[Epub ahead of print]. 16 5 NR Crizotinib Crizoti nib (n = 151) 11.1 (9.1-13.1) 10.4 (7.7-14.6) HR (95% CI) 0.47 (0.34-0.65) 0.50 (0.36-0.70) P Valu e <.001 <.001 Slide credit: clinicaloptions
J-ALEX: Efficacy Outcome Alectinib (n = 103) Crizotinib (n = 104) HR (99.6826% CI); P Value ORR by Investigator (ITT population) ORR, % (95% CI) CR or PR, n 85.4 (78.6-92.3) 88 70.2 (61.4-79.0) 73 -- ORR a by IRF ORR, % (95% CI) CR or PR, n (n = 83) 91.6 (85.6-97.5) 76 (n = 90) 78.9 (70.5-87.3) 71 -- a In pts with measurable disease at baseline by IRF. Alectinib showed consistent favorable treatment effect vs crizotinib for multiple prognostic factors Brain metastases: HR: 0.08 (95% CI: 0.01-0.61) Nokihara H, et al. ASCO 2016. Abstract 9008.
Conclusions In pts with advanced or metastatic ALK+ NSCLC, first-line treatment with alectinib provided greater clinical benefit vs crizotinib Prolonged median PFS: HR 0.47 (95% CI: 0.34-0.65; P <.0001) Delayed time to CNS progression Favorable toxicity Investigators conclude alectinib is the new first-line standard of care for pts with advanced ALK+ NSCLC Initial alectinib potentially superior to sequential crizotinib and alectinib based on large median PFS benefit Shaw A, et al. ASCO 2017. Abstract LBA9008.
ROS1 Fusion in Advanced NSCLC Most common in younger pts, never-smokers, adenocarcinoma, high-grade histology [1] Frequency: 1.2% to 1.7% overall [2] Several variants identified with different activation mechanisms; clinical significance unknown [3] FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3, KDELR2-, and CCDC6- Testing: Vysis break apart FISH (> 15% cells with split signal in 50 nuclei scored) [4-6] ROS PCR, IHC Crizotinib active; FDA approved in March 2016 for ROS1-positive NSCLC [7] 1. Bergethon K, et al. J Clin Oncol. 2012;30:863-870. 2. Davies KD, et al. Clin Cancer Res. 2012;18:4570-4579. 3. Takeuchi K, et al. Nat Med. 2012;18:378-381. 4. Gu TL, et al. PLoS One. 2011;6:e15640. 5. Birch AH, et al. PLoS One. 2011;6:e28250. 6. Lee J, et al. Cancer. 2013;119:1627-1635. 7. Shaw AT, et al. ASCO 2012. Abstract 7508.
BRAF V600E Mutation in Advanced NSCLC Occurs predominantly in pts with adenocarcinoma, [1] both those with a history of smoking and neversmokers [2,3] Frequency: 1% to 2% overall [3] Testing: NGS (1 assay approved by FDA) Dabrafenib plus trametinib active; approved for BRAF V600E-positive metastatic (FDA [4] ) or advanced (EU [5] ) NSCLC 1. Chen D, et al. PLoS One. 2014;9:e101354. 2. Paik PK, et al. J Clin Oncol. 2011;29:2046-2051. 3. Planchard D, et al. Lancet Oncol. 2016;17:984-993. 4. Dabrafenib [package insert]. 2017. 5. EMA. Tafinlar product information. 2017.
Advanced NSCLC (Molecular Biomarker Positive) EGFR mutation positive ALK positive ROS1 positive BRAF V600E positive PD-L1 positive First line Erlotinib, afatinib, or gefitinib Alectinib, ceritinib, or crizotinib Crizotinib Dabrafenib/ trametinib Pembrolizumab Progression EGFR T790M mutation positive Osimertinib EGFR T790M mutation negative Alectinib, brigatinib, or ceritinib dependent on previous therapy Second line and beyond Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker
Immune Checkpoint Inhibitors in Pretreated Advanced NSCLC: Randomized Late-StageTrials CheckMate 017 CheckMate 057 Squamous Stage IIIB/IV (N = 272) Nivolumab Docetaxel Nonsquamous Stage IIIB/IV (N = 582) Nivolumab Docetaxel Advanced NSCLC with 1% PD-L1+ tumor cells (N = 1034) KEYNOTE-010 Pembrolizumab (2 mg/kg) Pembrolizumab (10 mg/kg) Docetaxel Advanced NSCLC (2L/3L) (N = 1225) OAK Atezolizumab Docetaxel
OS (%) OS (%) CheckMate 017 and 057: Kaplan-Meier Estimates of OS CheckMate 017 (SQ NSCLC) CheckMate 057 (non-sq NSCLC) 100 Nivolumab (n=135) Docetaxel (n=137) Events, n (%) 110 (81) 128 (93) 100 Nivolumab (n=292) Docetaxel (n=290) Events, n (%) 228 (78) 247 (85) 80 Median OS, mo (95% CI) 9.2 (7.3, 12.6) 6.0 (5.1, 7.3) 80 Median OS, mo (95% CI) 12.2 (9.7, 15.1) 9.5 (8.1, 10.7) HR (95% CI) 0.62 (0.47, 0.80) HR (95% CI) 0.75 (0.63, 0.91) 60 Nivolumab 60 Nivolumab 40 20 Δ18% 1-yr OS=24% 1-yr OS=42% Δ15% Docetaxel 2-yr OS=23% 40 20 Δ12% 1-yr OS=39% Δ13% 1-yr OS=51% 2-yr OS=16% Docetaxel 2-yr OS=29% 2-yr OS=8% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (Months) Time (Months) Based on February 2016 DBL. Symbols refer to censored observations. Minimum follow-up for survival: 24.2 months.borghaei H et al. Poster presentation at ASCO 2016. 9025.
OS (%) OS (%) KEYNOTE-010: Overall Survival at TPS 1% and TPS 50% 1% PD-L1 Expression 10 900 80 2 vs 10 mg/kg: 70 60 HR 1.17, 95% CI 0.94, 50 1.45 40 30 Pembro 2 mg/kg 20 Pembro 10 mg/kg 10 Docetaxel 0 0 5 10 15 20 25 Time (mos) 50% PD-L1 Expression 10 900 2 vs 10 mg/kg: 80 HR 1.12, 95% CI 0.77, 70 1.62 60 50 40 30 Pembro 2 mg/kg 20 Pembro 10 mg/kg 10 Docetaxel 0 0 5 10 15 20 25 Time (mos) Treatment Arm Median (95% CI), mo Rate at 1 yr Pembro 2 mg/kg 10.4 (9.4, 11.9) 43.2% Pembro 10 mg/kg 12.7 (10.0, 17.3) 52.3% HR* (95% CI) P value 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) 0.0008 <0.0001 Docetaxel 8.5 (7.5-9.8) 34.6% Treatment Arm Pembro 2 mg/kg Pembro 10 mg/kg Median (95% CI), mo 14.9 (10.4, NR) 17.3 (11.8, NR) HR* (95% CI) P value 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) 0.0002 <0.0001 Docetaxel 8.2 (6.4, 10.7) * Comparison of pembrolizumab vs docetaxel. Analysis cut-off date: September 30, 2015. Herbst RS et al. Oral presentation at ESMO Asia 2015. 32
Overall Survival (%) Overall survival, ITT (n = 850) HR, 0.73 a (95% CI, 0.62, 0.87) P = 0.0003 Minimum follow up = 19 months Atezolizum Docetaxel Median 9.6 mo (95% CI, 8.6, 11.2) Median 13.8 mo (95% CI, 11.8, 15.7) Months Barlesi et al, Atezolizumab Phase III OAK Study.
PD-L1 testing requirements with approved agents in 2l+ nsclc OPDIVO (Nivolumab) 1 KEYTRUDA (Pembrolizumab) 2 TECENTRIQ (Atezolizumab) US PI Metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDAapproved therapy for these aberrations prior to receiving OPDIVO patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. Metastatic non-small cell lung cancer who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA approved therapy for these aberrations prior to receiving TECENTRIQ Companion Diagnostic Not Required Required as per FDA approval. PD-L1 IHC 22C3 pharmdx diagnostic test by Dako Essential for safe and effective use of a drug Not Required 1. US Prescribing Information, Opdivo. October 2015 2. US Prescribing Information, Keytruda. October 2015 3. US Prescribing Information Tecentriq October 2016 34
KEYNOTE-024: Study design A phase III, randomized, open-label study of pembrolizumab vs platinum-doublet chemotherapy as first-line therapy in patients with advanced or metastatic NSCLC that expresses PD-L1 in 50% of tumor cells N=305 Key Inclusion Criteria Advanced or metastatic, previously untreated NSCLC PD-L1+ tumor expression 50% No EGFR sensitizing mutation or ALK translocation ECOG PS 1 Primary endpoint: PFS Secondary endpoints: ORR, OS, safety, and tolerability R Pembrolizumab 200 mg Q3W Given until disease progression, intolerable toxicity, investigator decision, or completion of 35 cycles Optional crossover after disease progression Investigator choice of platinum-based chemotherapy For 4 6 cycles Pembrolizumab is currently not approved for 1L advanced/metastatic NSCLC. Investigator choice of chemotherapy included carboplatin AUC 5/6 IV Q3W or cisplatin 75 mg/m 2 IV Q3W plus pemetrexed 500 mg/m 2 IV Q3W or gemcitabine 1250 mg/m 2 IV Q3W or carboplatin AUC5/6 IV Q3W plus paclitaxel 200 mg/m 2 IV Q3W. Clinicaltrials.gov. NCT02142738. Accessed September 08, 2016.
Progression-Free Survival 50% PD-L1+ PFS, % 100 90 80 70 60 50 62% 50% Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016. Events, n Median, mo HR P Pembro 73 10.3 Chemo 116 6.0 0.50 (0.37-0.68) 40 30 20 10 0 0 3 6 9 12 15 18 Time, months 48% 15% <0.001
Proposed treatment algorithm (no actionable biomarker) Good PS Clinical (PS) Poor PS Progressi on * Bevacizumab eligible Plt/pemetrexed (or other*) ± bevacizumab, carboplatin/pemetrexed + pembrolizumab Bevacizumab, pemetrexed, bevacizumab + pemetrexed, gemcitabine, pembrolizumab Histologic Nonsquamous Squamous Single-agent or combination chemotherapy Clinical Bevacizumab ineligible Platinum/pemetrexed (or other*), carboplatin/pemetrexed + pembrolizumab Pemetrexed, gemcitabine, or pembrolizumab Based on prior therapy: atezolizumab, nivolumab, pembrolizumab (if PD-L1+), or other systemic agents including docetaxel ± ramucirumab, pemetrexed, gemcitabine Platinum doublet* or cisplatin/gemcitabine/ necitumumab Docetaxel or gemcitabine Based on prior therapy Based on prior therapy: atezolizumab, nivolumab, pembrolizumab (if PD-L1+), or other systemic agents including docetaxel ± ramucirumab, gemcitabine, or possibly afatinib First line Maintenance Second line and beyond
Conclusions Testing for actionable molecular mutations and PD-L1 expression is critical for all patients with newly-diagnosed advanced NSCLC Approved targeted therapies are available for EGFR mutations, ALK rearrangements, ROS1 rearrangements, and the BRAF V600E mutation PD-1/PD-L1 inhibitors have revolutionized advanced NSCLC care First-line: pembrolizumab is approved for high PD-L1 tumor expression ( 50%) and, for nonsquamous histology, in combination with carboplatin/pemetrexed Progressive disease: atezolizumab, nivolumab, and pembrolizumab ( 1% PD-L1) are approved Vigilance for immune-related AEs along with rapid intervention is key to optimal management
Survival Survival Where We Are Now Where We Want to Be? Time Time Control Targeted therapies Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341. Immune checkpoint blockade Combinations/sequencing