Immunotherapy for NSCLC: Current State of the Art and Future Directions. H. Jack West, MD Swedish Cancer Institute Seattle, Washington, United States

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2 Immunotherapy for NSCLC: Current State of the Art and Future Directions H. Jack West, MD Swedish Cancer Institute Seattle, Washington, United States

3 Which of the following statements regarding immunotherapy for the treatment of NSCLC is most accurate? 1. Patients who have received steroids in the past are not eligible for immunotherapy 2. Patients with higher levels of tumor-infiltrating lymphocytes respond better to immunotherapy 3. Only patients with tumors that express high levels of PD-L1 respond to PD-1 inhibitors 4. Immune-checkpoint blockade is only effective in patients with squamous histology

4 PD-1 and PD-L1 Inhibitors in Previously Treated Advanced NSCLC

5 5 Reasons Immunotherapy for NSCLC Has Been So Exciting 3) Variable response onset, even >6 months to best response 4) Responses lasting months to YEARS after treatment discontinued 2) Activity in squamous as good as or better than nonsquamous patients 5) Responses ongoing >2-3 years! 1) Heavily pretreated patients Number of Prior Systemic Treatment Regimens N % Gettinger SN, et al. J Clin Oncol. 2015;33(18):

6 Patterns of Response to Checkpoint Inhibitors Brahmer JR, et al. N Engl J Med. 2012;366(26):

7 West, HJ. JAMA Oncol. 2015;1(1):115. Pseudoprogression

8 Nivolumab in Squamous NSCLC Chemo-pretreated (1 st line) advanced squamous NSCLC N = 272 Primary endpoint: overall survival R A N Nivolumab 3 mg/kg IV q 14 days until PD D Docetaxel 75 mg/m 2 IV q 21 days until PD Variable Objective response Brahmer JR, et al. N Engl J Med. 2015;373(2): Nivolumab (n = 135) Docetaxel (n = 137) Number of patients % of patients (95% CI) 20 (14-28) 9 (5-15) Estimated odds ratio (95% CI) 2.6 ( ) P value.008 Duration of response, months Median NR 8.4 Range 2.9 to to 15.2

9 Overall Survival Benefit With Nivolumab Brahmer JR, et al. N Engl J Med. 2015;373(2):

10 Which of the following statements regarding the use of PD-L1 expression of a biomarker for PD-1 inhibitors in NSCLC is accurate? 1. Patients with <1% expression of PD-L1 do not respond to nivolumab 2. Patients who do not express PD-L1 should not receive PD-1 inhibitors 3. Higher PD-L1 expression predicts for greater magnitude of response to pembrolizumab 4. Patients with higher PD-L1 expression are more likely to experience immune-related adverse events

11 Should We Be Selecting Patients for Nivolumab Based on PD-L1 Expression? NO. Brahmer JR, et al. N Engl J Med. 2015;373(2):

12 Toxicity Differences Strongly Favor Nivolumab Brahmer JR, et al. N Engl J Med. 2015;373(2):

13 Impact of Nivolumab on Squamous NSCLC Nivolumab, now FDA-approved for chemotherapy-pretreated squamous NSCLC, is the clear standard of care for second-line squamous NSCLC There is no role for testing for PD-L1 expression or contingencies based on the results in this setting

14 Nivolumab in Nonsquamous NSCLC Chemo-pretreated (1 st line) advanced nonsquamous NSCLC N = 582 Primary endpoint: overall survival R A N D Nivolumab 3 mg/kg IV q 14 days until PD Docetaxel 75 mg/m 2 IV q 21 days until PD Nivolumab (n = 292) Docetaxel (n = 290) ORR (95% CI) 19% (15, 24) 12% (9, 17) Odds Ratio (95% CI) 1.75 (1.1, 2.6) P value.0246 Best overall response, % Complete response 1 1 Partial response Stable disease Progressive disease Unable to determine Median time to response, months (range) 2.1 (1.2, 8.6) 2.6 (1.4, 6.3) Media DOR, months (range) 17.2 (1.8, 22.6) 5.6 (1.2, 15.2) Ongoing response, % Borghaei H, et al. N Engl J Med. 2015;373(17):

15 Toxicity Differences Again Strongly Favor Nivolumab Treatment-Related Adverse Events Reported in 10% of Patients Nivolumab (n = 287) Docetaxel (n = 268) Any Grade, % Grade 3-4, % Any Grade, % Grade 3-4, % Total patients with an event Fatigue Nausea Decreased appetite Asthenia Diarrhea Peripheral edema Myalgia Anemia Alopecia Neutropenia Febrile neutropenia Leukopenia Borghaei H, et al. N Engl J Med. 2015;373(17):

16 Overall Survival Benefit With Nivolumab in Nonsquamous NSCLC Borghaei H, et al. N Engl J Med. 2015;373(17):

17 Responses to Nivolumab vs Docetaxel in Nonsquamous Advanced NSCLC Borghaei H, et al. N Engl J Med. 2015;373(17):

18 Progression-Free Survival Benefit With Nivolumab in Nonsquamous NSCLC Is there a subgroup who really does better with docetaxel? Should we do PD-L1 testing to individualize treatment recommendations? Borghaei H, et al. N Engl J Med. 2015;373(17):

19 Should We Be Selecting Nonsquamous Patients for Nivolumab Based on PD-L1 Expression? Paz-Ares L, et al. J Clin Oncol. 2015;33(Suppl): Abstract LBA109.

20 Which Nonsquamous NSCLC Patients Do and Do Not Benefit From Nivolumab? Borghaei H, et al. N Engl J Med. 2015;373(17):

21 Impact of Nivolumab on Nonsquamous NSCLC Nivolumab is now FDA approved as treatment for nonsquamous NSCLC Guidelines do not recommend testing for PD-L1 However, the argument can be made that it should be used for selection of second-line therapy in nonsquamous NSCLC As in squamous NSCLC, docetaxel +/- ramicirumab and EGFR TKI based therapies will be pushed out one line later (with significant attrition)

22 Pembrolizumab (MK3475) in NSCLC Expansion Cohorts: KEYNOTE-001 Nonrandomized (N = 33) PD-L1+ tumors 2 previous therapies Nonrandomized (N = 40) PD-L1- tumors 2 previous therapies Randomized (N = 144) PD-L1+ tumors 1 previous therapy Randomized (N = 45) PD-L1+ tumors Treatment naive Nonrandomized (N = 45) PD-L1+ tumors 1 previous therapy R (3:2) R (1:1) Pembro 10 mg/kg q 3 weeks Pembro 10 mg/kg q 2 weeks Pembro 10 mg/kg q 3 weeks Pembro 10 mg/kg q 2 weeks Pembro 2 mg/kg q 3 weeks Pembro 10 mg/kg q 3 weeks Pembro 10 mg/kg q 2 weeks Pembro 2 mg/kg q 3 weeks Response assessment Primary measure: ORR by RECIST v1.11 per independent central review Secondary measure: immune-related response criteria 2 per investigator assessment Pembrolizumab was given until disease progression, unacceptable toxicity, or death Garon EB, et al. N Engl J Med. 2015;372(21):

23 Pembrolizumab in First-Line or Previously Treated Advanced NSCLC Progression-Free Survival Overall Survival Garon EB, et al. N Engl J Med. 2015;372(21):

24 Pembrolizumab in Advanced NSCLC Pembrolizumab is FDA-approved (at 2 mg/kg dose every 3 weeks) for chemotherapy-pretreated PD-L1- positive (by companion diagnostic) advanced NSCLC independent of NSCLC histology, based on 61 pts treated at 10 mg/kg dose Definition of PD-L1 positive is debatable: specific test defines positive as 50% staining Will that be followed by clinicians and payers? How commonly will people test when nivolumab has no such requirement?

25 Which of the Following Was Observed in the KEYNOTE-010 Trial of Pembrolizumab Vs Docetaxel? 1. Both doses of pembrolizumab (2mg/kg and 10mg/kg) were equally effective in PD-L1+ patients 2. EGFR+ patients responded better to docetaxel 3. Docetaxel was more effective in patients who had <50% PD-L1 expression 4. Patient age was a strong predictor of outcome

26 KEYNOTE-010: Pembrolizumab vs Docetaxel as Second-Line Therapy in PD-L1+ Advanced NSCLC Chemo-pretreated (1 st line) PD-L1+ ( 1% by IHC) advanced nonsquamous NSCLC N = 1034 R A N D Pembrolizumab 2 mg/kg IV q 21 days until PD Pembrolizumab 10 mg/kg IV q 21 days until PD Docetaxel 75 mg/m 2 IV q 21 days until PD Primary endpoint: overall survival and progression-free survival, looking at 1) All patients, and 2) Subset with >50% PD-L1+ Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

27 KEYNOTE-010: Pembrolizumab vs Docetaxel, Overall Survival PD-L1 >50% Patients All (PD-L1+) Patients Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

28 KEYNOTE-010: Pembrolizumab vs Docetaxel, Overall Survival Older patients benefited from pembrolizumab Higher PD-L1 expression correlates with greater benefit from pembrolizumab, but lower PD-L1+ also benefit Archival tissue comparable to fresh Both adeno & squamous histologies show comparable benefit for pembrolizumab Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

29 KEYNOTE-010: Pembrolizumab vs Docetaxel, Progression-Free Survival Does Dose Matter for Pembrolizumab? PD-L1 >50% Patients All (PD-L1+) Patients If PD-L1 are equal for PD-L1 >50% but differences may emerge for all patients, the patients with 1-49% PD-L1+ must do (somewhat) worse at 2 mg/kg vs 10 mg/kg Differences must be more pronounced by dose for 1%-49% PD-L1+ Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

30 KEYNOTE-010: Response Rate ORR, % Pembrolizumab 2 mg/kg (n = 139) Pembrolizumab 10 mg/kg (n = 151) Docetaxel (n = 152) PD-L1 TPS 50% 30 (P<.0001*) 29 (P<.0001*) 8 PD-L1 TPS 1% 18 (P<.0005*) 18 (P<.0002*) 9 *Comparison of pembrolizumab vs docetaxel Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

31 KEYNOTE-010: Pembrolizumab vs Docetaxel,Toxicities Herbst RS, et al. Lancet Dec 18. [Epub ahead of print].

32 Which of the following characteristics would render a patient ineligible to receive immunotherapy? 1. History of smoking 2. EGFR mutation 3. Prior treatment with immunotherapy 4. Brain metastases 5. Uncontrolled multiple sclerosis

33 PD-L1 Expression on Tumor Cells (TC) and Immune Cells (IC) as Marker for Atezolizumab Response SP142 IHC assay is sensitive and specific for PD-L1 expression on both TC and IC Distinct TC and IC subpopulations exist at each of four cutoff levels [Gettinger SN, et al. J Clin Oncol. 2015;33(Suppl): Abstract 3015] Spira AI, et al. J Clin Oncol. 2015;33(Suppl): Abstract PD-L1 expression on TC and IC was independently predictive of response [Horn L, et al. J Clin Oncol. 2015;33(Suppl): Abstract Spigel DR, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8028.]

34 Phase II POPLAR Trial: Atezolizumab vs Docetaxel in Previously Treated NSCLC Chemo-pretreated (1-2 lines) Advanced nonsquamous NSCLC N = 287 Stratification: PD-L1 expression 0/1 vs 2/3 nonsquamous vs squamous 2 nd line vs 3 rd line R A N D Atezolizumab 1200 mg IV q 21 days until PD Docetaxel 75 mg/m2 IV q 21 days until PD Primary endpoint: OS in PD-L1 selected and ITT populations Secondary endpoints: overall safety as well as PFS, ORR, DoR in PD-L1 selected and ITT populations Spira AI, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8010.

35 POPLAR Trial: Overall Survival, All Patients (ITT) Spira AI, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8010.

36 POPLAR: OS Results by IHC Subgroup Spira AI, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8010.

37 POPLAR: PFS Results by IHC Subgroup Subgroup (% of enrolled patients) Spira AI, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8010.

38 Phase III OAK Trial: Atezolizumab vs Docetaxel in Previously Treated NSCLC Chemo-pretreated (1-2 lines) Advanced nonsquamous NSCLC N = 1100 Stratification: PD-L1 expression 0/1 vs 2/3 nonsquamous vs squamous 2 nd line vs 3 rd line R A N D Atezolizumab 1200 mg IV q 21 days until PD Docetaxel 75 mg/m 2 IV q 21 days until PD Primary endpoint: OS Secondary endpoint: ORR, PFS, DoR, safety National Institutes of Health. Available at: Accessed March 14, 2016.

39 How Valuable and How Reliable is PD-L1 Testing?

40 PD-L1 NSCLC Sample IHC Staining PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive Negative Weak positive (1% to 49%) Strong positive (50% to 100%) Gandhi L, et al. Cancer Res. 2014;74(19Suppl): Abstract CT105.

41 PD-L1 IHC Assays: Variability Contributes to Unreliability Pembrolizumab* (Anti PD-1) Nivolumab* (Anti PD-1) Durvalumab (Anti PD-L1) Atezolizumab (Anti PD-L1) Clones 22C SP26 SP14 Machines utilized Link 48 Link 48 BenchMark ULTRA BenchMark ULTRA Compartment TM TM TM TC/IC Variables % of cells % of cells % of cells % of cells Definition of positive PD-L1(+): > 1% Strong(+): > 50% PD-L1(+): > 1% Strong(+): > 5% PD-L1(+): 25% TC / IC 3(+) TC / IC 2(+) TC / IC 1(+) TC / IC 0( ) *FDA-approved assays

42 Toxicity Issues With Checkpoint Inhibitors: General Considerations

43 Which of the following adverse events is NOT considered to be immunerelated? 1. Pneumonitis 2. Rash 3. Hypertension 4. Colitis 5. Hepatotoxicity

44 PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events Any grade 1 AE or Isolated hypothyroidism Symptom management or replacement therapy for hypothyroidism Grade 2 pneumonitis, nephritis, colitis, hepatitis Symptomatic hypophysitis Any grade 3 AE Hold PD-1 tx and administer steroids After improvement to grade 1, taper steroids over at least 1 month Continue PD-1 tx and monitor Resume if: AE remains at grade 0/1 after steroid taper Permanently discontinue if: No improvement to grade 1 within 12 weeks Cannot taper steroids to 10 mg/day of prednisone or equivalent within 12 weeks Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.

45 PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events Grade 3/4 pneumonitis Grade 3/4 nephritis Grade 3/4 infusion-related reaction Any life-threatening or grade 4 AE Any severe or grade 3 recurrent AE Hepatitis associated with AST/ALT >5 x ULN AST/ALT 50% from baseline lasting 1 week* Total bilirubin >3 x ULN Initiate steroid therapy Permanently discontinue PD- 1 tx *In patients with liver metastasis who begin treatment with grade 2 elevation of AST/ALT Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.

46 New Settings, New Combinations

47 PACIFIC Trial: MEDI4736 vs Placebo After Chemoradiation in Unresectable NSCLC Randomized, double-blind, placebo-controlled phase III trial Locally advanced, unresectable stage III NSCLC Completed concurrent Platinum-based chemo/radiation N = 702 R A N D MEDI-4736 IV until progression or up to 12 months Placebo IV until progression or up to 12 months Primary endpoint: OS Secondary endpoint: ORR, PFS, DoR, safety National Institutes of Health. Available at: Accessed March 14, 2016.

48 Adjuvant Checkpoint Inhibitor Therapy for Resected Early-Stage NSCLC Stage I-IIIa NSCLC s/p resection, then adjuvant cisplatin-based chemo PD-L1 + for TC3 or IC3 N = 760 R A N D Atezolizumab 1200 mg IV every 3 weeks x 16 Best supportive care Primary endpoint: Secondary endpoint: DFS for 1) all patients and 2) stage II & IIIa patients OS for 1) all patients and 2) stage II & IIIa patients

49 A Roadmap of Immunotherapy- Tumor Interactions Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL Trafficking of T cells to tumors 5 Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists 2 6 Recognition of cancer cells by T cells CARs Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy 1 7 Killing of cancer cells Anti PD-L1 Anti PD-1 IDO inhibitors Chen DS, et al. Immunity. 2013;39(1):1-10.

50 How Does Immunotherapy Compare to First Line Chemotherapy? IMpower 110 Stage IV Non-squamous NSCLC PD-L1 + N = 400 R A N D Atezolizumab 1200 mg IV every 3 weeks Cisplatin or carboplatin/pemetrexed IV every 3 weeks Primary endpoint: progression-free survival National Institutes of Health. Available at: Accessed March 14, Cancer Grace Website. Available at: Accessed March 14, 2016.

51 Which of the following results were observed when the combination of ipilimumab + nivolumab was compared to nivolumab in a trial in melanoma? 1. The combination resulted in unacceptable toxicity 2. The combination was less effective than single-agent nivolumab 3. The combination improved survival only in PD-L1- tumors 4. The combination improved survival in regardless of PD-L1 expression

52 CheckMate 067: Ipilimumab vs Nivolumab vs Ipi/Nivo Combination for Melanoma Ipilimumab Previously untreated Stage III or IV melanoma No PD-L1 requirement N = 945 R A N D Nivolumab Ipilimumab Nivolumab Primary endpoints: progression-free survival and overall survival Larkin J, et al. N Engl J Med. 2015;373(1):23-34.

53 CheckMate 067: Ipi vs Nivo vs Ipi/Nivo Combination Therapy for Melanoma Combination significantly superior to nivo alone for PD-L1-negative tumors No differences for PD-L1 positive tumors No overall survival data yet Larkin J, et al. N Engl J Med. 2015;373(1):23-34.

54 Immunotherapy Monotherapy or Doublet vs Standard Chemotherapy CheckMate-227 Trial Stage IV NSCLC squamous or non-squamous no restriction by PD-L1 expression N = 1980 R A N D Primary endpoints: overall survival & Progression-free survival Nivolumab q 2 weeks Nivo q3 weeks + Ipilimumab q3 weeks x4 treatments Cisplatin or carboplatin + pemetrexed (nonsquam) or gemcitabine (squam) Nivo q2 weeks National Institutes of Health. Available at: Accessed March 14, 2016.

55 Immune Checkpoint Inhibitors in NSCLC: The Present Nivolumab (regardless of PD-L1 expression) and pembrolizumab (in PD-L1+) are FDA approved in chemo-pretreated advanced NSCLC. Other PD-1 and PD-L1 inhibitors demonstrate comparable efficacy. Efficacy and side-effect profiles are more similar than different. Cross-resistance unknown (including PD-L1 inhibitor after PD-1, and vice versa) All checkpoint inhibitors demonstrate greater efficacy in PD-L1+ patients Greater expression correlated with greater benefit, but PD-L1+ is neither necessary nor sufficient for response Optimal test, threshold, all still unknown

56 Immune Checkpoint Inhibitors in NSCLC: The Future A wide range of checkpoint inhibitors are being studied as first-line therapy (in PD-L1+ or less selected pts) In combination with standard-of-care chemo or targeted therapy Compared to/instead of standard-of-care chemo or targeted therapy In combination with CTLA-4 inhibitors Anticipate broad PD-L1 testing, especially as these therapies enter first-line setting (to select who gets 1 st line, single agent vs combination) Other/better biomarkers sought Checkpoint inhibitors are being tested in curative settings for NSCLC, also for other thoracic cancers

57 My View: Immuno-Oncology is the 3 rd Big Wave in Systemic Therapy for Cancer Conventional Chemotherapy Targeted Therapy (esp for Targeted Populations) Immuno- Oncology