LUNG CANCER. ASCO Poster Review. Paolo Bironzo Department of Oncology University of Torino S. Luigi Gonzaga Hospital Orbassano (TO)

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1 LUNG CANCER ASCO Poster Review Paolo Bironzo Department of Oncology University of Torino S. Luigi Gonzaga Hospital Orbassano (TO)

2 Agenda Locally advanced NSCLC: ETOP-NICOLAS phase 2 trial (abstract #8510, S. Peters et al) Immunotherapy: Clinical and molecular characteristics of long term responders (abstract #9022, H. Rizvi et al) Safety and PROs with Nivo+Ipi vs Chemo from CheckMate227 (abstract #9020, M. Reck et al) HRQoL from KEYNOTE-189 (abstract #9021, MC. Garassino et al) Oncogene addicted: Tepotinib in MET ex14 mutant NSCLC (abstract #9016, E. Felip et al) TAK-788 for ex20 EGFR mutant and HER2 mutant NSCLC (abstract #9015, RC. Doebele) Alectinib in treatment naive ALK+ NSCLC (abstract #9043, DR Camidge et al) MPM: Novel insights into MPM (abstract #8516, M. Ladanyi et al.)

3 Agenda Locally advanced NSCLC: ETOP-NICOLAS phase 2 trial (abstract #8510, S. Peters et al)

Safety cohort (58 pts) Median number of nivolumab cycles: 8 (range

4%) experienced a serious AE Most frequently AEs: fatigue (41.

0%) including 2 SAEs Grade 5 AE: 1 oesophageal fistula; 2 strokes.

3%) G3 33% in the cohort CONCLUSIONS: The addition of nivolumab to

4 Safety cohort (58 pts) Median number of nivolumab cycles: 8 (range 1-17) 52 (89.7%) experienced an AE 24 (41.4%) experienced a serious AE Most frequently AEs: fatigue (41.4%), anaemia (41.4%) including 1 SAEs, nausea (31.0%) including 2 SAEs Grade 5 AE: 1 oesophageal fistula; 2 strokes. Pneumonitis: 13 (22.4%) G1-2; 6 (10.3%) G3 33% in the cohort CONCLUSIONS: The addition of nivolumab to CT/RT is safe and tolerable The 1-year PFS will be evaluated according to the hierarchial design in the expanded cohort of 74 patients. Adapted from Peters S. Abstract #8510 ASCO 2018

5 Agenda Immunotherapy: Clinical and molecular characteristics of long term responders (abstract #9022, H. Rizvi et al) Safety and PROs with Nivo+Ipi vs Chemo from CheckMate227 (abstract #9020, M. Reck et al) HRQoL from KEYNOTE-189 (abstract #9021, MC. Garassino et al)

6 Adapted from Rizvi H. Abstract #9022 ASCO 2018

7 TMB and PD-L1 expression in long-term responders. TMB and PD-L1 expression among long-term and short-term responders. TP53, ARID1A, KEAP1, PDGFRA genes are associated with LTR. Depth of response is associated with LTR. Adapted from Rizvi H. Abstract #9022 ASCO 2018

8 Adapted from Reck M. Abstract #9020 ASCO 2018

Symptoms: Lung Cancer Symptom Scale (higher scores= worsening symptoms) QoL: EQ-5D index (higher scores = better QoL) Early and sustained

9 PROs assessed at every cycle for the first 6 months, then every 6 weeks and at follow-up visits 1 and 2. For each scale, minimally important difference (MID) defined as the smallest change considered to be clinically meaningful. Symptoms: Lung Cancer Symptom Scale (higher scores= worsening symptoms) QoL: EQ-5D index (higher scores = better QoL) Early and sustained improvement in QoL of N+I versus chemotherapy in pts wth high TMB. Longer time to symptoms deterioration of N+I versus chemotherapy in pts with high TMB. Adapted from Reck M. Abstract #9020 ASCO 2018

10 Adapted from Gandhi L. AACR 2018

QLQ-LC13 (higher scores = worsening symptoms) Pembro/Pem/Plat NR (10-2-NR) vs

11 All patients who received at least one dose of treatment and completed 1 PRO instrument QoL & Symptoms = EORTC QLQ-C30 (higher score = better QoL) Symptoms: QLQ-LC13 (higher scores = worsening symptoms) Pembro/Pem/Plat NR (10-2-NR) vs Placebo/Pem/Plat 7.0 (4.8-NR) HR 0.81 ( ), p Adapted from Garassino MC. Abstract #9021 ASCO 2018

12 Agenda Oncogene addicted: Tepotinib in MET ex14 mutant NSCLC (abstract #9016, E. Felip et al) TAK-788 for ex20 EGFR mutant and HER2 mutant NSCLC (abstract #9015, RC. Doebele) Alectinib in treatment naive ALK+ NSCLC (abstract #9043, DR Camidge et al)

13 Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: Phase II trial. [Abstract 9016] Felip E, Horn L, Patel JD, Sakai H, Scheele J, Bruns R, Paik PK, on behalf of the VISION study group. Single-arm open-label phase II trial Tepotinib (MET TKI type Ib inhibitor) 500 mg QD. Designed for 60 tissue positive (Oncomine) and 60 ctdna positive (Guardant) MET exon 14 patients. 44% overlapped both groups. No prior TKI allowed. Efficacy: best overall response rate (IRC) mdor (n:12): months (95% CI: ) Adapted from Camidge DR. ASCO 2018

5%) of patients (none drug related) TEAEs led to treatment discontinuation in 5 patients (13.2%) 8 (21.

14 Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: Phase II trial. [Abstract 90165] Felip E, Horn L, Patel JD, Sakai H, Scheele J, Bruns R, Paik PK, on behalf of the VISION study group. Safety results Grade 4 AEs reported in 4 (10.5%) of patients (none drug related) TEAEs led to treatment discontinuation in 5 patients (13.2%) 8 (21.1%) patients had 1 dose reduction 2 deaths not related to treatment (1 progression, 1 bronchopulmonary hemorrage) Conclusions: tepotinib 500 mg QD has promising activity in MET exon 14 skipping mutants NSCLC. Its safety profile is as expected based on previous studies. Recruitment is ongoing. Adapted from Camidge DR. ASCO 2018

First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non-small cell lung cancer (NSCLC).

Phase I/II first-in-human, openlabel, multi-centre study. 34 patients, 88% 2 previous lines of therapy.

15 First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non-small cell lung cancer (NSCLC). [Abstract 9015] Doebele RC, Riely GJ, Spira AI, Horn L, Piotrowska Z, Botelho Costa D, Neal JW, Zhang S, Reichmann W, Kerstein D, Li S, Janne PA. Phase I/II first-in-human, openlabel, multi-centre study. 34 patients, 88% 2 previous lines of therapy. HER2 ex20 insertions:1-2% of NSCLC; EGFR ex20 insertion: 5-10% of EGFR mutations 3 over 4 confirmed responders with EGFR exon20 are ongoing Median time on treatment days (range, 139 to 311+ days) Adapted from Camidge DR. ASCO 2018

16 First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non-small cell lung cancer (NSCLC). [Abstract 9015] Doebele RC, Riely GJ, Spira AI, Horn L, Piotrowska Z, Botelho Costa D, Neal JW, Zhang S, Reichmann W, Kerstein D, Li S, Janne PA. 180 mg QD not-tolerable 160 mg QD RP2D but: - lot of EGFR WT related side effects (diarrhea, skin rash) and some upper GI sideeffects - 1 DLT (1 grade 3 mucositis) Conclusions: proof of principle that EGFR (and HER2) ex20 mutations can be actionable. Data extremely small and immature. 3/6 patients treatd with 160 mg QD required dose reductions Adapted from Camidge DR. ASCO 2018

Phase 3 randomized trial of Alectinib vs

17 Phase 3 randomized trial of Alectinib vs Crizotinib in untreated advanced ALK+ NSCLC. 303 randomized patients. Median follow-up 27.8 months. At the updated data cut-off 47.4% of patients receiving AL vs 76.8% receiving CZ in the ITT population had experienced PD or death. HR 0.43 (95% CI ) mpfs 34.8 (17.7-NE) for AL vs 10.9 ( ) for CZ. Adapted from Camidge DR, Abstract #9043, ASCO 2018

18 Agenda MPM: Novel insights into MPM (abstract #8516, M. Ladanyi et al.)

analysis, DNA methylation, reverse-phase protein

Significant negative findings: No targetable hot

fusions involving EWSR1 or RTKs No SV40 sequences

multiplatform analysis defined 4 novel prognostic

19 74 cases form the TCGA. Whole exome, mrna,mirna, non-coding RNA seq; CN analysis, DNA methylation, reverse-phase protein array profiling. Significant negative findings: No targetable hot spots mutations in RTKs, MAPK pathway nor PI3/AKT No fusions involving EWSR1 or RTKs No SV40 sequences but BAP1 inactivation in 57% Integrative multiplatform analysis defined 4 novel prognostic subsets. Novel phenotype (3%): extensive LOH, no asbestos, younger, female predominance (M:F=1:4) Adapted from Ladanyi M, Abstract #8516, ASCO 2018

20 VISTA expression is associated with epithelioid component and is also highly correlated with mesothelin expression. Rooms for VISTA checkpoint inhibitors? Adapted from Ladanyi M, Abstract #8516, ASCO 2018

21 Conclusions Locally advanced NSCLC: ETOP-NICOLAS phase 2 trial: CT/RT plus Nivo met safety endpoint will it also meet efficacy? Immunotherapy: Clinical and molecular characteristics of long term responders: a large retrospective study highlighting factors affecting LTR (but with some risk of bias). Safety and PROs with Nivo+Ipi vs Chemo from CheckMate227: PROs correlate with efficacy. HRQoL from KEYNOTE-189: adding IOs to CT doesn t affects QoL in untreated advanced NSqC-NSCLC. Oncogene addicted: Tepotinib in MET ex14 mutant NSCLC: another possible therapeutic option but more data are needed. TAK-788 for ex20 EGFR mutant and HER2 mutant NSCLC: a possible step forward but not all ex20 are made the same and beware of toxicities. Alectinib in treatment naive ALK+ NSCLC: alectinib is keeping promises MPM: Novel insights into MPM: new landscapes deserving further studies.

22 Thank you

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