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![• Key results (cont.)
– Pembrolizumab + ipilimumab showed antitumour activity with all responses ongoing at
data cut-off
• Conclusions
– Preliminary data demonstrate robust and durable antitumour activity with an
acceptable toxicity profile for pembrolizumab + ipilimumab in unselected
patients with recurrent NSCLC
– The use of a lower ipilimumab dose did not appear to negatively impact efficacy
8011: Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for
advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D – Patnaik A et al
Patnaik et al. J Clin Oncol 2015; 33 (suppl): abstr 8011
Pembro 10 mg/kg +
IPI 1 or 3 mg/kg,
(n=6)
Pembro 2 mg/kg +
IPI 1 mg/kg,
(n=12)
Total
(n=18)
ORR, n (%) [95%CI] 3 (50) [12, 88] 4 (33) [10, 65] 7 (39) [17, 64]
DCR, n (%) [95%CI] 6 (100) [54, 100] 9 (75) [43, 94] 15 (83) [59, 96]
Best overall response, n (%)
CR
PR
SD ≥6 weeks
PD
1 (17)
2 (33)
3 (50)
0
0
4 (33)
5 (42)
3 (25)
1 (6)
6 (33)
8 (44)
3 (17)](https://image.slidesharecdn.com/wbvjbv2qg6svg76q0bic-signature-00f4c4d096b7bd6e1bb05b55f88850f9ce0ca6124b2323f2bd00ddd507b81dc2-poli-150905153634-lva1-app6891/75/ImmunoOncology-in-Lung-Cancer-26-2048.jpg)
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ImmunoOncology in Lung Cancer
- 1. Lung Cancer –Taming through a ‘Novel Pathway’ #immunoncology! Ashok .K. Vaid Medical Oncology & Hematology Medanta Cancer Institute : Medanta – The Medicity, Gurgaon (New Delhi), India Excerpts from ASCO 2015
- 2. • Lung CancerBackground • Immunity and Cancer • Biomarkers- ASC0 2015 • Advanced NSCLC • Other Malignancies SCLC and mesothelioma
- 3. Lung Cancer Incidenceand Mortality • New cases in 2013: 228,190 – 40% with stage IV disease at presentation (~ 90,000) • ~ 160,000 deaths in 2013, comparable to prostate, pancreas, breast, and colon cancer combined • 5-year relative survival rate: 13% overall (2% for patients with distant-stage) disease NCI. Non-small-cell lung cancer treatment (PDQ®). ACS. Cancer facts & figures: 2013. Estimated Cancer Deaths by Site, 2013 Other Cancers Lung Cancer 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0 Lung cancer Prostate Pancreas Breast Colon
- 4. 0 5 10 15 20 1975 1980 19851990 1995 2000 2005 Year of Diagnosis 5-yearOS(%) Gain in 5-year OS over the past 3 decades in lung cancer http://seer.cancer.gov, Accessed Nov. 2014
- 5. History of Therapyin Advanced NSCLC: FDA Approval Dates First line Second line Third line Maintenance Not approved 1970 1980 1990 2000 Median OS (mos) 12+ ~ 6 ~ 2-4 BSC Single-agent platinum Doublets Bevacizumab + PC Carboplatin* 1989 Erlotinib Pemetrexed 2004 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Vinorelbine 1994 Docetaxel 2002 Bevacizumab 2006 Gefitinib 2003 Standard therapies *Label does not include NSCLC-specific indication Pemetrexed 2008/2009 Histology-directed therapy ~ 8-10 Cisplatin* 1978 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
- 6. Role of immunesystem in cancer prevention • Eliminate/ suppress viral infections: protection from viral induced tumors. • Prevent establishment of an inflammatory environment • Identify and eliminate tumor cells based on the expression of tumor-specific antigens: cancer immuno surveillance • Cytotoxic T cells play a key role in cancer immune response
- 7. Cytotoxic T cellsplay a key role in cancer immune response • Regulated by a range of immune cells. • T cells- potent mediators of anti-tumor immunity • T cell immune response: – recognize a "non-self" target – Involves processing & presentation – Cytotoxic T cells: effector cells – Activated, search of cells bearing that unique MHC Class I + peptide
- 8.
- 9. CTLA-4: cytotoxic Tlymphocyte associated protein 4 PD-1: programed cell death protein 1 Mellman Nature 2011 T cell response is regulated by co-stimulatory (“Go”)and co-inhibitory/checkpoint (“Stop”) factors “Brakes”“Accelerator” Immune checkpoint inhibitors Attenuate T cell response Promote T cell response T cell regulation is important! Prevents immune mediated damage
- 10. Immune checkpoint inhibitors PharmaceuticalCompound Status CTLA-4 inhibitor BMS Ipilimumab Approved for melanoma AZ/MedImmune Tremelimumab Phase III PD-1 inhibitor BMS Nivolumab Approved for melanoma, NSCLC (SCC) MSD Pembrolizumab Approved for melanoma Curetech Pidilizumab Phase II Novartis PDR001 Phase I-II PD-L1 inhibitor Genentech/ Roche Atezolizumab Phase III AZ/MedImmune Durvalumab Phase III Merck Serono Avelumab Phase III
- 11.
- 12. Primary endpoint • OS Studyobjective • To investigate the efficacy and safety of atezolizumab (MPDL3280A) in NSCLC and correlation of response with PD-L1 expression on tumour-infiltrating immune cells (IC) and/or tumour cells (TC) • PD-L1 expression was evaluated by IHC using the SP142 antibody assay • Patients were scored as TC0, 1, 2 or 3 and IC0, 1, 2 or 3 Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010 Secondary endpoints • PFS, ORR, duration of response, safety 8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al Stratification • PD-L1 IC expression (0 vs. 1 vs. 2 vs. 3) • Histology (squamous vs. non-squamous) • Prior chemotherapy regimens (1 vs. 2) R PD Loss of clinical benefit Key patient inclusion criteria • Metastatic or locally advanced NSCLC • At least 1 prior platinum- based chemotherapy (n=287) Docetaxel 75 mg/m2 q3w (n=143) Atezolizumab 1200 mg IV q3w (n=144)
- 13. • Key results –Across the ITT interim population, survival was similar between atezolizumab and docetaxel (HR 0.77; 95%CI 0.55, 1.06; p=0.11) – However, OS with atezolizumab increased with increasing PD-L1 expression (TC/IC ≥1); those with <1% expression did not derive benefit relative to docetaxel 8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010 p=0.070 p=0.026 p=0.024 p=0.70 p=0.11 Interim OS Subgroup (% of enrolled patients) TC3 or IC3 (16%) TC2/3 or IC2/3 (37%) TC1/2/3 or IC1/2/3 (68%) TC0 or IC0 (32%) ITT (N=287) 0.46 0.56 0.63 1.12 0.77 0.2 1 2 Hazard ratioa In favour of atezolizumab In favour of docetaxel a Unstratified HR for subgroups and stratified HR for ITT. Data cut-off Jan 30, 2015
- 14. • Key results(cont.) – Patients with higher PD-L1 expression also had better outcomes with atezolizumab than with docetaxel (ORR 38% vs. 13% in patients with the highest levels) – Atezolizumab was well tolerated with fewer treatment-related Grade 3/4 AEs (12% atezolizumab; 39% docetaxel) despite a longer treatment duration (3.7 vs. 2.1 months) • Conclusions – Improved survival with atezolizumab was associated with increasing PD-L1 expression – PD-L1 is a predictive diagnostic biomarker that can be used to identify those patients with NSCLC who will benefit most from atezolizumab therapy Spira et al. J Clin Oncol 2015; 33 (suppl): abstr 8010 8010: Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR) – Spira AI et al 38 22 18 8 1513 15 18 10 15 0 10 20 30 40 50 TC3 or IC3 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 TC0 and IC0 ITT Atezolizumab (n=144) Docetaxel (n=143) ORR(confirmed, RECISTv1.1),%
- 15. Gainor et al.J Clin Oncol 2015; 33 (suppl): abstr 8012 8012: Clinical correlation and frequency of PD-L1 expression in EGFR-mutant and ALK-rearranged NSCLC – Gainor JF et al • Study objective – To evaluate PD-L1 expression patterns and clinical outcomes in EGFR-mutant and ALK- rearranged NSCLC patients receiving TKIs • Study design – Retrospective analysis of IHC data of biopsy and resection specimens from patients with metastatic, EGFR-mutant (n=68) and ALK-rearranged (n=28), NSCLC. Expression of PD-L1 in >5% tumour cells was defined as positive. CD8+ tumour-infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0−3) • Key results – No significant difference was observed in PFS or OS between PD-L1 (+) and (-) patients. OS on ALK TKIs was shorter among PD-L1 (+) patients (p=0.045) • Conclusion – EGFR-mutant and ALK-rearranged lung cancers can express PD-L1 and show CD8+ immune infiltrates, but most do not have both. This may explain the low response rates observed with PD-1 inhibitors in never/light smokers EGFR-mutant ALK-rearranged n/N (%) Pre-TKI Post-TKI p Pre-TKI Post-TKI p PD-L1 (+) 9/62 (15) 16/64 (25) 0.181 11/21 (52) 3/14 (21) 0.089 CD8+ TILs (2-3+) 12/62 (19) 13/65 (20) 1.000 6/18 (33) 0/14 (0) 0.024 PD-L1 (+) and CD8+ TILs (2-3+) 3/61 (5) 8/64 (13) 0.207 3/18 (17) 0/14 (0) 0.238
- 16. 7560: The associationof T cells with survival in mesothelioma – Chee SJ et al Chee et al. J Clin Oncol 2015; 33 (suppl): abstr 7560 • Study objective – To assess whether tumour infiltrating lymphocyte (TIL) density identifies patients with mesothelioma and ongoing immune attack who may benefit from immune activation • Study design – Tissue microarrays were performed on a consecutive series of 213 samples from patients with mesothelioma; slides were stained for CD3, CD4, CD8 and CD45RO – The mean score was used to account for tumour heterogeneity • Key results – There was no association between density of tumour infiltrating CD3 (p=0.224), CD4 (p=0.205) and CD8 (p=0.243) cells and survival outcomes – Two variables were significantly associated with better survival: • High (>0.61) CD4:CD8 ratio (p=0.007) • Low CD45RO level (p=0.002) • Conclusion – A high CD4:CD8 ratio and low density of CD45RO memory T cells are associated with better survival in patients with mesothelioma
- 17.
- 18. LBA109: Phase III,randomized trial (CheckMate 057) of nivolumab (NIVO)- PD 1 inhibitor- versus docetaxel in advanced non-SQ NSCLC – Paz-Ares L et al Primary endpoint • OS Secondary endpoints • ORR, PFS, safety, efficacy by PD-L1 expression, QoL R PD or toxicity PD or toxicity Stratification • Prior maintenance therapy • Line of therapy (2nd vs. 3rd) Key patient inclusion criteria • Stage IIIB/IV non-squamous NSCLC • Pre-treatment (archival or recent) tumor samples available for PD-L1 testing • ECOG PS 0–1 • Failed 1 prior platinum doublet (n=582) Docetaxel 75 mg/m2 IV q3w (n=290) Nivolumab 3 mg/kg IV q2w (n=292) Study objective • To evaluate the efficacy and safety of nivolumab vs. docetaxel in patients with advanced non-squamous NSCLC after failure of platinum-based doublet chemotherapy Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109
- 19. LBA109: Phase III,randomized trial of nivolumab (NIVO) versus docetaxel in advanced (non-SQ) NSCLC – Paz-Ares L et al • Key results – Nivolumab was associated with a 27% reduction in risk of death Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109 OS 0 3 6 9 12 15 18 21 24 27 292 232 194 169 146 123 62 32 9 0 290 244 194 150 111 88 34 10 5 0 Time (months) Nivolumab Docetaxel 1-year OS rate=51% 1-year OS rate=39% Symbols represent censored observations Nivolumab Docetaxel Number of Patients at Risk OS(%) Nivolumab (n=292) Docetaxel (n=290) mOS, months 12.2 9.4 HR 0.73 (96%CI 0.59, 0.89); p=0.0015 100 90 80 70 60 50 40 30 20 10 0
- 20. LBA109: Phase III,randomized trial of nivolumab (NIVO) versus docetaxel in advanced non-squamous cell (non-SQ) NSCLC – Paz-Ares L et al • Key results • PD-L1 expressors benefitted more from nivolumab than PD-L1 non-expressors – Nivolumab improved survival vs. docetaxel in previously treated patients with advanced non-squamous NSCLC with efficacy being correlated with PD-L1 expression Paz-Ares et al. J Clin Oncol 2015; 33 (suppl): abstr LBA109 PD-L1 expression level Nivolumab (n) Docetaxel (n) Unstratisfied HR (95% CI) Interaction p-value* OS ≥1% 123 123 0.59 (0.43, 0.82) 0.0646 <1% 108 101 0.90 (0.66, 1.24) ≥5% 95 86 0.43 (0.30, 0.63) 0.0004 <5% 136 138 1.01 (0.77, 1.34) ≥10% 86 79 0.40 (0.26, 0.59) 0.0002 <10% 145 145 1.00 (0.76, 1.31) Not quantifiable at baseline 61 66 0.91 (0.61, 1.35) PFS ≥1% 123 123 0.70 (0.53, 0.94) 0.0227 <1% 108 101 1.19 (0.88, 1.61) ≥5% 95 86 0.54 (0.39, 0.76) <0.0001 <5% 136 138 1.31 (1.01, 1.71) ≥10% 86 79 0.52 (0.37, 0.75) 0.0002 <10% 145 145 1.24 (0.96, 1.61) Not quantifiable at baseline 61 66 1.06 (0.73, 1.56) PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable 0.25 0.5 1.0 2.0 Nivolumab Docetaxel
- 21. Next step • Combinationof immune targeted drugs
- 22. Study objective • Toinvestigate the antitumour activity and tolerability of the combination of MEDI4736 (M) and tremelimumab (T) in patients with advanced NSCLC who have failed to respond or relapsed after any line of therapy Study design • Phase 1b, open-label, dose-escalation study in patients with advanced NSCLC • Treated with M (3, 10, 15, or 20 mg/kg q4w or 10 mg/kg q2w) and T (1, 3, or 10 mg/kg q4w for 6 doses then q12w for 12 doses) administered for 12 months Key results G, grade; D/C, discontinuation 3014: Phase Ib study of MEDI4736, a PD-L1 antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in advanced NSCLC – Antonia SJ et al Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 3014 N (%) M3q4w T1 n=3 M10q4w T1 n=3 M15q4w T1 n=18 M20q4w T1 n=18 M10q2w T1 n=17 M10q4w T3 n=3 M15q4w T3 n=14 M20q4w T3 n=6 M10q2w T3 n=11 M15q4w T10 n=9 All cohorts n=102 Any AE 3 (100) 3 (100) 17 (94) 14 (78) 15 (88) 3 (100) 14 (100) 6 (100) 11 (100) 9 (100) 95 (93) Any G3/G4 AE 0 (0) 2 (67) 11 (61) 8 (44) 6 (35) 3 (100) 10 (71) 6 (100) 7 (64) 8 (89) 61 (60) Any deaths 0 (0) 1 (33) 3 (17) 2 (11) 2 (12) 0 (0) 3 (21) 2 (33) 1 (9) 1 (11) 15 (15)* SAE 1 (33) 2 (67) 11 (61) 7 (39) 4 (24) 2 (67) 10 (71) 6 (100) 5 (45) 8 (89) 56 (55) AE to D/C 1 (33) 1 (33) 4 (22) 1 (6) 2 (12) 2 (67) 5 (36) 4 (67) 3 (27) 4 (44) 27 (26) Related AE 1 (33) 3 (100) 11 (61) 9 (50) 12 (71) 3 (100) 12 (86) 5 (83) 10 (91) 8 (89) 74 (73) Related G3/G4 0 (0) 2 (67) 7 (39) 4 (22) 3 (18) 2 (67) 6 (43) 5 (83) 5 (45) 7 (78) 41 (40) Related deaths 0 (0) 1 (33)† 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (17)‡ 0 (0) 0 (0) 2 (2) Relates SAE 0 (0) 1 (33) 4 (22) 4 (22) 1 (6) 2 (67) 6 (43) 5 (83) 4 (36) 7 (78) 34 (33) Related AE to D/C 0 (0) 1 (33) 2 (11) 1 (6) 0 (0) 2 (67) 4 (29) 3 (50) 3 (27) 4 (44) 20 (20) *Death excluding disease progression=8%; †Related death due to polymyositis (complications arising from drug-related myasthenia gravis); ‡Related death due to neuromuscular disorder. Red box=selected phase 3 dose.
- 23. 3014: Phase Ibstudy of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC – Antonia SJ et al KEY RESULTS Lowest frequency of AEs was in the T1 cohorts and generally increased for doses above T1 (previous slide) Treatment-related AEs across all cohorts Grade 3/4 occurred in 40% of patients (most frequently colitis, diarrhoea, elevated lipase and elevated liver function tests) 31% of patients used corticosteroids and 20% discontinued therapy Treatment-related AEs among patients treated at M20 q4w T1 Grade 3/4 occurred in 22% of patients (most frequently diarrhoea, pruritus, rash and elevated AST/ALTs) 17% of patients used corticosteroids and 6% discontinued therapy Clinical activity in patients with PD-L1 positive tumours in the T1 cohorts: ORR of 33% (95%CI 13, 59) DCR at ≥16 weeks of 44% (95%CI 14, 79) Clinical activity in patients with PD-L1 negative tumours in the T1 cohorts: ORR of 38% (95%CI 14, 68) DCR at ≥16 weeks of 62% (95%CI 32, 86) Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 3014 Conclusions The combination of M + T has a manageable safety profile with evidence of clinical activity, including in PD-L1-negative disease The M20 q4w T1 dose combination will be investigated in phase 3 studies AST, aspartate aminotransferase; ALT, alanine aminotransferase
- 24. Study objective • Toevaluate the efficacy and safety of MEDI4736, a human IgG1 monoclonal anti-PD-L1 antibody, combined with gefitinib (G) in patients with NSCLC Study design • Phase 1, dose escalation (n=10) and dose expansion (n=15) study • Expansion study undertaken in TKI-naïve patients with EGFR sensitising mutant NSCLC • Arm 1: MEDI4736 10 mg/kg q2w plus G 250 mg qd • Arm 2: G 250mg qd for 4 weeks followed by MEDI4736 10 mg/kg q2w + G 250 mg qd Key results • All patients in the dose-escalation phase demonstrated tumour reductions Conclusions • MEDI4736 in combination with gefitinib shows acceptable tolerability and tumour reductions with early signs of activity in TKI-naïve EGFR mutant population 3047: Safety and tolerability results from a phase I study of MEDI4736, (PD-L1 antibody), combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC) : – Creelan BC et al Creelan et al. J Clin Oncol 2015; 33 (suppl): abstr 3047 Cohort A* (n=3) Cohort B† (n=6) Changeintargetlesion diameterfrombaseline,% 70 60 50 40 30 20 10 0 –10 –20 –30 –40 –50 0 8 16 24 32 40 48 Time (weeks) xx *Cohort A: G 250 mg qd + MEDI4736 3 mg/kg q2w; †Cohort B: G 250 mg qd + MEDI4736 10 mg/kg q2w
- 25. 8011: Phase 1study of pembrolizumab- PD 1 inhibitor- (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D – Patnaik A et al • Study objective – To evaluate in a phase I study pembrolizumab + ipilimumab in patients with recurrent NSCLC of any histology (interim results provided) • Key results – As of 31 March 2015, 18 patients have been enrolled: • 3 in the pembrolizumab 10 mg/kg + ipilimumab 1 mg/kg, 3 in the pembrolizumab 10 mg/kg + ipilimumab 3 mg/kg, and 12 in the pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg – No DLTs have been reported – 15 patients experienced treatment-related AEs; 2 led to discontinuation (1 each with pembrolizumab 10 mg/kg + ipilimumab 3 mg/kg and pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg) Patnaik et al. J Clin Oncol 2015; 33 (suppl): abstr 8011
- 26. • Key results(cont.) – Pembrolizumab + ipilimumab showed antitumour activity with all responses ongoing at data cut-off • Conclusions – Preliminary data demonstrate robust and durable antitumour activity with an acceptable toxicity profile for pembrolizumab + ipilimumab in unselected patients with recurrent NSCLC – The use of a lower ipilimumab dose did not appear to negatively impact efficacy 8011: Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D – Patnaik A et al Patnaik et al. J Clin Oncol 2015; 33 (suppl): abstr 8011 Pembro 10 mg/kg + IPI 1 or 3 mg/kg, (n=6) Pembro 2 mg/kg + IPI 1 mg/kg, (n=12) Total (n=18) ORR, n (%) [95%CI] 3 (50) [12, 88] 4 (33) [10, 65] 7 (39) [17, 64] DCR, n (%) [95%CI] 6 (100) [54, 100] 9 (75) [43, 94] 15 (83) [59, 96] Best overall response, n (%) CR PR SD ≥6 weeks PD 1 (17) 2 (33) 3 (50) 0 0 4 (33) 5 (42) 3 (25) 1 (6) 6 (33) 8 (44) 3 (17)
- 27. Other malignancies SCLC andMesothelioma
- 28. Primary endpoints • ORRper RECIST v1.1, safety Study objective • To assess the efficacy and safety of pembrolizumab, an anti-PD-1 monoclonal antibody, in patients with PD-L1+ SCLC *Defined as membranous PD-L1 expression in ≥1% of cells in tumour nests or positive bands in stroma; †Every 8 weeks for the first 6 months; every 12 weeks thereafter 7502: Pembrolizumab (MK-3475- PD 1 inhibior) in patients with extensive-stage SCLC: Preliminary safety and efficacy results from KEYNOTE-028 – Ott PA et al Ott et al. J Clin Oncol 2015; 33 (suppl): abstr 7502 Secondary endpoints • PFS, OS, duration of response Pembrolizumab 10 mg/kg q2w CR, PR or SD Key patient inclusion criteria • SCLC • PD-L1 positivity* • Failure of standard therapy • ≥1 measurable lesion • ECOG PS 0 or 1 • Absence of autoimmune disease or interstitial lung disease (n=20) Treat for 24 months or until PD/toxicity Confirmed PD/ toxicity Discontinue pembrolizumab Response assessment†
- 29. • Key results –Pembrolizumab showed promising antitumour activity – No unexpected toxicity • Most common AEs occurring in ≥2% were arthralgia and asthenia (15% of patients) followed by nausea and rash (10%) • One treatment-related death was reported (colitis) and one treatment-related discontinuation (grade 2 autoimmune thyroiditis) • Conclusions – Pembrolizumab was generally well tolerated and demonstrated preliminary promising antitumour activity in patients with PD-L1+ SCLC 7502: Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028 – Ott PA et al * Ott et al. J Clin Oncol 2015; 33 (suppl): abstr 7502 Best overall response n % 95%CI ORR* 7 35 15−59 Complete response 0 0 0−17 Partial response 7 35 15−59 Stable disease 1 5 0−25 Progressive disease 9 45 23−69 No assessment# 3 15 3–38
- 30. Primary endpoint • ORRper RECIST v1.1 Study objective • To assess the efficacy and safety of nivolumab, an IgG4 PD-1 immune checkpoint inhibitor, with or without ipilimumab, a CTLA-4 checkpoint inhibitor, in previously treated SCLC patients 7503: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032 : Antonia SJ et al Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 7503 Secondary endpoints • Safety, PFS, OS, biomarker analysis Key patient inclusion criteria • SCLC • Progressive disease • ≥1 prior therapy including first-line platinum-based therapy • Unselected by PD-L1 expression (n=128) Nivolumab 1 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=3) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV q3w for 4 cycles (n=47) Nivolumab 3 mg/kg IV q2w (n=40) Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=38) Nivolumab 3 mg/kg IV q2w Data from this cohort were not presented
- 31. • Key results –Clinical responses occurred in patients regardless of PD-L1 expression • Conclusions – Nivolumab alone or in combination with ipilimumab showed activity and durable responses in patients with SCLC and progressive disease – Nivolumab alone or in combination with ipilimumab had a manageable safety profile – These regimens will be explored in future trials of patients with SCLC 7503: Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032: Antonia SJ et al Antonia et al. J Clin Oncol 2015; 33 (suppl): abstr 7503 Bestreductionfrombaselinein targetlesion(%) 150 125 100 75 50 25 0 –25 –50 –75 –100 Nivolumab + Ipilimumab <1% PD-L1 ≥1% PD-L1 Not evaluable* Confirmed responders 150 125 100 75 50 25 0 –25 –50 –75 –100 Nivolumab Evaluable samples (40 of 96) PD-L1 expression level, n (%) <1% ≥1% Nivolumab (n=22) 15 (68) 7 (32) Nivolumab + ipilimumab (n=18) 12 (67) 6 (33)
- 32. Side effects ofimmunotherapy Hypophysitis Thyroiditis Adrenal insufficiencyEnterocolitis Dermatitis, itch, vitiligo, alopecia Motor & sensory neuropathy Hepatitis Pneumonitis Pancreatitis Arthritis Ocular: scleritis/uveitis Renal toxicity: GN Lower incidence of imAEs with PD-1/PD-L1 inhibitors compared with Ipilimumab (but not devoid of them) Most frequent toxicities reported are mild fatigue, rash, pruritis, diarrhoea and colitis
- 33. Conclusion 1. Immunotherapies representa new pillar of treatment for NSCLC. 2. PD-L1 is a potential predictive biomarker. 3. Development of biomarker key to further development as a single agent and in combination with other therapies. 4. Unique side effects consistent with the immune mechanism of action.
- 34.