Applying Emerging Immunotherapy Data to NSCLC Clinical Practice

Transcription

1 Applying Emerging Immunotherapy Data to NSCLC Clinical Practice Jarushka Naidoo, MBBCH Upper Aerodigestive Division, Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medicine Baltimore, Maryland

2 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) Outline Brief Introduction to Cancer Immunotherapy A Newly Diagnosed Patient with NSCLC Diagnostic Evaluation Choice of reatment How to Manage the Patient Receiving Immunotherapy Special Patient Populations Previous Autoimmune Conditions Brain Metastases Patients With Oncogene-Driven NSCLC

3 Immunotherapy in Cancer he cancer-immunity cycle Chen DS, et al. Immunity. 2013;39(1):1-10.

4 Immunotherapy in Cancer he cancer-immunity cycle Lymph node CLA4 CLA4 CLA4 Chen DS, et al. Immunity. 2013;39(1):1-10.

5 Immunotherapy in Cancer he cancer-immunity cycle Lymph node CLA4 CLA4 CLA4 Chen DS, et al. Immunity. 2013;39(1):1-10.

6 Immunotherapy in Cancer he cancer-immunity cycle Lymph node CLA4 CLA4 OX40 GIR PD-L1 GAL9 CLA4 HVEM VISA CD137 CD28 BLA4 LAG3 Chen DS, et al. Immunity. 2013;39(1):1-10.

7 Immunotherapy in Cancer he cancer-immunity cycle Lymph node CLA4 CLA4 OX40 GIR PD-L1 GAL9 CLA4 HVEM VISA CD137 CD28 BLA4 LAG3 Chemotherapy Radiation argeted herapy Vaccines IFN-alpha GM-CSF Anti-CD40 Anti-CLA4 Anti-CD137 Anti-OX40 IL2 Anti-CXCL12 Anti-VEGF CAR -cells Immune Checkpoint mabs Chen DS, et al. Immunity. 2013;39(1):1-10.

8 Immunotherapy in Cancer he cancer-immunity cycle Lymph node CLA4 PD-1 CLA4 OX40 GIR PD-L1 GAL9 CLA4 HVEM VISA CD137 CD28 BLA4 LAG3 Chemotherapy Radiation argeted herapy Vaccines IFN-alpha GM-CSF Anti-CD40 Anti-CLA4 Anti-CD137 Anti-OX40 IL2 Anti-CXCL12 Anti-VEGF CAR -cells Immune Checkpoint mabs Chen DS, et al. Immunity. 2013;39(1):1-10.

9 he Human Immune system he ultimate anticancer therapy? Specificity: virtually infinite antigen recognition Adaptability: based on tumor genetic & epigenetic changes Memory: durable responses even after drug discontinuation Universality: potential antitumor effect regardless of tumor type Naidoo J, et al. Ann ransl Med. 2016;4(9):177.

10 he Human Immune system he ultimate anticancer therapy? Specificity: virtually infinite antigen recognition Adaptability: based on tumor genetic & epigenetic changes Memory: durable responses even after drug discontinuation Universality: potential antitumor effect regardless of tumor type umor ypes With Objective Response to Anti-PD-1/PD-L1 Melanoma Non-small cell lung carcinoma Renal cell carcinoma Urothelial carcinoma Head and neck carcinoma Merkel cell carcinoma MSI-high colorectal carcinoma Biliary tract carcinoma Ovarian carcinoma Breast carcinoma Anal carcinoma Mesothelioma Gastric adenocarcinoma Hodgkin lymphoma Hepatocellular carcinoma Naidoo J, et al. Ann ransl Med. 2016;4(9):177.

11 Immunotherapy in NSCLC Nivolumab vs. Docetaxel in Second-line: Squamous NSCLC 272 patients: 135 (nivolumab); 137 (docetaxel) Brahmer J, et al. N Engl J Med. 2015;373(2):

12 Immunotherapy in NSCLC Nivolumab vs. Docetaxel in Second-line: Non-Squamous NSCLC 582 patients: 292 (nivolumab); 290 (docetaxel) Borghaie H, et al. N Engl J Med. 2015;373(17):

13 Immunotherapy in NSCLC Pembrolizumab vs. Docetaxel in PD-L1+ NSCLC 1033 patients: 344 (pembro 2mg/kg), 346 (pembro 10mg/kg), 343 (docetaxel) All patients (PD-L1 >1%) PD-L1 >50% PD-L1 Immunohistochemical assay Garon EB, et al. N Engl J Med. 2015;372(21): Herbst RS, et al. Lancet. 2016;387(10027):

14 Newly Diagnosed NSCLC Diagnostic evaluation A 58-year-old woman presents with newly diagnosed metastatic lung adenocarcinoma involving the liver, mediastinal lymph nodes, and bones. Which of the following tests make up the standard diagnostic evaluation for this patient? A. Body imaging (C or PE/C) B. Brain imaging (C or MRI) C. PD-L1 testing on tumor biopsy D. EGFR and ALK testing on tumor biopsy E. All of the above

15 NCCN Guidelines PD-L1 testing now part of standard workup for stage IV NSCLC

16 PD-L1+ NSCLC (>50%) KEYNOE-024 KEYNOE-024 (NC ) Patients with PD-L1+ NSCLCs benefit from pembrolizumab vs chemotherapy Reck M, et al. N Engl J Med Oct 8. [Epub ahead of print].

17 PD-L1+ NSCLC (>50%) KEYNOE-024 Progression-Free Survival Overall Survival 5.7-month PFS benefit HR = 0.5, P< % vs 15% progression-free at 1 year Median OS results not mature HR = 0.6, P = % vs 54% alive at 1 year Reck M, et al. N Engl J Med Oct 8. [Epub ahead of print].

18 Newly Diagnosed NSCLC Diagnostic evaluation he patient requires additional tumor sampling for PD-L1 testing Which of the following tests is most suitable? A. SP142 test on core biopsy B. 22C3 test on core biopsy C. 22C3 test on fine-needle aspiration D test on fine-needle aspiration E. It doesn t matter; they are all the same

19 PD-L1 esting KEYNOE-024 Soria JC, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 33LBA.

20 PD-L1 esting Are all PD-L1 tests created equal? Assay Patient Selection Cutoffs Used in rials Nivolumab 28-8 none umor cells: 1%, 5% Pembrolizumab 22C3 umor cells >50% umor cells: 1%, 5%, 50% Atezolizumab SP142? umor cells; 1%, 5%, 10% Immune cells: 1%, 5%, 10% Durvalumab SP263? umor cells>25% Avelumab 73-10? umor cells: >1%, >5%, >10% Immune cells: >10% sao et al, ESMO 2016

21 PD-L1 esting IASLC Blueprint Study phase I: Aims 1. Compare staining characteristics of 4 PD-L1 IHC assays in NSCLC 2. Assess if they can be interchanged when used to select patients Hirsch FR, et al. Cancer Res. 2016;76(14 Suppl): Abstract.

22 PD-L1 esting IASLC Blueprint Study phase I: Results Analytical Evaluation Results by hree Readers *Data points represent the mean score from 3 pathologists for each assay for each case 1. 3 PD-L1 IHCs ( C3, SP263) have similar analytical performance in NSCLC samples when assessed by 3 readers (% cells positive, range) 2. SP142 labels fewer tumor cells 3. All assays label immune cells, less analytical performance than tumor cells 4. Higher concordance between observers for tumor-cell vs immune-cell staining sao et al, ESMO 2016

23 PD-L1 esting IASLC Blueprint Study phase I: Results Can clinical scoring algorithms be interchanged? % of cases show discrepant results for PD-L1 between assays 2. Potential for different results if assays and cutoffs are mismatched 3. Recommend to use each therapeutic-diagnostic combination as it is approved sao et al, ESMO 2016

24 PD-L1 esting KEYNOE-024 PD-L1 expression: - Core needle biopsy/excisional biopsy/ resected tissue - FFPE tissue: at least 100 tumor cells - PD-L1 IHC 22C3 pharmdx - Role for PD-L1 testing on cytology samples unknown ALAS of PD-L1 testing in NSCLC - Blueprint phase II project - Validation of phase I in different sample types (resection, biopsy, cytology) - interobserver concordance among 20 pathologists - Compare needle biopsy vs resection sample vs cytology in same patient Reck M, et al. N Engl J Med Oct 8. [Epub ahead of print]. sao et al, ESMO 2016.

25 Newly Diagnosed NSCLC Choice of treatment he patient s tumor biopsy demonstrates that the tumor is: EGFR wild-type, ALK FISH negative, and PD-L1 60% using the 22C3 assay. Which of the following treatment options would you select for this patient? A. Carboplatin + Pemetrexed B. Carboplatin + Pemetrexed + Bevacizumab C. Clinical trial D. Pembrolizumab

26 Newly Diagnosed NSCLC Management of patient receiving Immunotherapy he patient starts treatment with pembrolizumab and reports a clinical improvement in cough and bone pain. After 3 doses of therapy, the patient has her first restaging imaging, which demonstrates stable appearances but development of 1 new tumor lesion. What would you do next? A. Continue pembrolizumab B. Stop pembrolizumab; consider second-line chemotherapy C. Stop pembrolizumab; consider second-line anti-pd-l1 therapy D. Hold pembrolizumab temporarily

27 Pseudoprogression Unique response kinetics with immune checkpoint blockade Immune-Related Response Criteria (irrc) - Response assessment to characterize atypical responses, seen in 5% -10% cases - Patients with melanoma treated with ipilimumab (phase II program) - irrc (SD + PR) had comparable outcomes to RECIS 1.1 (SD + PR) - Suspected radiologic progression is reassessed with C >4 weeks after initial C Key Difference RECIS 1.1 irrc umor measurement Unidimensional Bidimensional arget lesions Maximum 5 Maximum 15 New lesion Progressive disease 10 visceral and 5 cutaneous lesions may be added to the sum of the products of the 2 perpendicular largest diameters of all index lesions Complete Response Disappearance of all target and nontarget lesions; no new lesions; LN <10 mm short axis Partial Response Progressive Disease Stable Disease >30% decrease from baseline >20% + 5 mm absolute increase in tumor burden >50% decrease from baseline >25% increase in tumor burden. New lesions added to calculation of tumor burden Neither progressive disease nor partial response Wolchok JD, et al. Clin Cancer Res. 2009;15(23): Hodi FS, et al. J Clin Oncol. 2016; 34(13):

28 Pseudoprogression Does this occur with Anti-PD-1/PD-L1? Patients with melanoma on KEYNOE-001 (2 or 10mg/kg pembrolizumab, n=655) Patients assessed by both RECIS 1.1 and central irrc, imaging >28 weeks (n=327) Early pseudoprogression: >25% in tumor burden week 12, no PD next scan Delayed pseudoprogression: >25% in tumor burden post week 12, no PD next scan Hodi FS, et al. J Clin Oncol. 2016;34(13):

29 Pseudoprogression Does this occur with Anti-PD-1/PD-L1? Patients with melanoma on KEYNOE-001 (2 or 10mg/kg pembrolizumab, n=655) Patients assessed by both RECIS 1.1 and central irrc, imaging >28 weeks (n=327) Early pseudoprogression: >25% in tumor burden week 12, no PD next scan Delayed pseudoprogression: >25% in tumor burden post week 12, no PD next scan Phenomenon of potential pseudoprogression needs to be studied rigorously in other solid tumors Hodi FS, et al. J Clin Oncol. 2016;34(13):

30 Newly Diagnosed NSCLC Management of patient receiving Immunotherapy he patient continues therapy with subsequent shrinkage of all tumor lesions. After 3 months of pembrolizumab, he reports a new dry cough and shortness of breath. he chest C scan is below. What could be the cause(s) of this clinical scenario? A. Lung infection B. Progressive metastatic disease C. Pneumonitis D. All of the above

31 IR-oxicity Management General principles Inflammatory processes can affect any organ system Distinct from chemotherapy side effects Evaluation and management are unique May be exacerbated by underlying autoimmune conditions/presence of autoantibodies Patients with autoimmune conditions not requiring >10 mg daily prednisone/equivalent may receive therapy 1. Always suspect an autoimmune toxicity 2. Rule out competing diagnoses (?infection?progression) 3. Identify the toxicity (diarrhea vs colitis) 4. Grade the toxicity Naidoo J, et al. Ann Oncol. 2015;26(12):

32 Pneumonitis Incidence Naidoo J, et al. J Clin Oncol Sept 19. [Epub ahead of print].

33 Pneumonitis Challenges How do we diagnose pneumonitis? How do we manage it? Grade 1 Close observation Grade 2 Drug withholding Oral steroid taper over 4-6 weeks Grade 3-4 Discontinue immunotherapy IV steroid, oral steroid taper if improves other immunosuppression if worsens, 48hr Is this: Infection? Progression? Pneumonitis? What are the outcomes with treatment?

34 Pneumonitis Variable radiologic features COP-like (n=5) Ground-Glass Opacities (n=10) Hyper- Sensitivity (n=2) Interstitial (n=6) NOS (n=4) Associated with: NSCLC histology (P =.03), Immunosuppressive herapy (P =.06) Mild (n=15) Moderate (n=6) Severe (n=6) Naidoo J, et al. J Clin Oncol Sept 19. [Epub ahead of print].

35 Pneumonitis Variable timing of onset Naidoo J, et al. J Clin Oncol Sept 19. [Epub ahead of print].

36 Pneumonitis Variable pathologic features A Cellular interstitial pneumonitis (n = 4) D Granulomas (n = 2) B Organizing pneumonia (n = 2) E Eosinophils (n = 3) C Diffuse alveolar damage (n = 1) Naidoo J, et al. J Clin Oncol Sept 19. [Epub ahead of print].

37 Newly Diagnosed NSCLC Management of patient receiving immunotherapy What is the appropriate management of this patient? A. Continue immunotherapy; monitor closely as an outpatient B. Hold immunotherapy; monitor closely as outpatient C. Hold immunotherapy; treat with antibiotics as an outpatient D. Hold immunotherapy; treat with corticosteroids +/- empiric antibiotics; consider hospitalization and bronchoscopy E. Permanently discontinue immunotherapy

38 Adapted Management Algorithm Pneumonitis with immune checkpoint blockade Grade Investigations Management Follow-up 1 Asymptomatic, radiologic changes only Radiologic imaging (High-resolution C chest) Consider holing immunotherapy Monitor for symptoms every 3 days Repeat C every cycle If develops symptoms, treat as higher grade 2 Mild/moderate new symptoms 3-4 Severe/lifethreatening new symptoms or worsening hypoxia Microbial assessment where necessary Consider pulmonary/ infectious diseases consults and bronchoscopy Withhold immunotherapy Monitor for symptoms daily Oral prednisone 1 mg/kg/day or equivalent Discontinue immunotherapy Hospitalization IV methylprednisolone 2-4 mg/kg/day or equivalent Prophylactic antibiotics If improves to grade 1 within 3 days of supportive care, resume immunotherapy at next dose If persistent beyond 3 days, discontinue immunotherapy After symptoms improve, taper steroids over 1 month After symptoms improve to grade 1 or baseline, taper steroids over 6 weeks If worsens in 48 hours, consider additional immunosuppression (infliximab, cyclophosphamide, mycophenolate mofetil) Naidoo J, et al. Ann Oncol. 2015;26(12):

39 Special Patient Populations Autoimmune conditions A 72-year-old gentleman with metastatic squamous lung carcinoma presents for consideration of second-line therapy after progression following 4 cycles of carboplatin/nab-paclitaxel. he patient has a history of SLE for which he receives immunosuppressive therapy. Is this patient suitable for second-line immunotherapy? A. Yes, since his cancer has progressed after chemotherapy B. Yes, since patients with autoimmune conditions can have responses to anti-pd-1 C. No; these patients have been excluded from clinical studies of immunotherapy in NSCLC, and no published data exist in this population D. No, since the patient has squamous NSCLC

40 Anti-PD-1 in Autoimmune Disease/After iraes in Metastatic Melanoma reated With Ipilimumab 52/119 patients treated with PD-1 had autoimmune disease - RR = 33% - 20 (38%) patients had a mild flare of autoimmune disease requiring immunosuppression, 2 (4%) patients discontinued treatment due to flare - 15 (29%) developed other iraes and 4 (8%) discontinued treatment. - 67/119 had prior ipilimumab iraes requiring immunosuppression - RR = 40% - 2 (3%) patients had a recurrence of the same ipilimumab iraes - 23 (34%) developed new iraes (21% grade 3+); 8 (12%) discontinued anti-pd-1 Menzies AM, et al. Ann Oncol Sept 29. [Epub ahead of print].

41 Special Patient Populations Brain metastases A 69-year-old woman with metastatic lung adenocarcinoma presents with acute onset headache and is found to have a solitary brain metastasis as well as multiple lung nodules. he brain metastasis is resected and is found to be 67% PD-L1+ (22C3 assay) What treatment approach may be suitable for this patient and why? A. Pembrolizumab, since the tumor is PD-L1+ B. Pembrolizumab, since the tumor is PD-L1+ and immunotherapy may be efficacious in patients with brain metastases C. Whole-brain radiation followed by carboplatin + pemetrexed D. Whole-brain radiation followed by carboplatin + pemetrexed + bevacizumab

42 Anti-PD-1 in NSCLC and Melanoma Brain Metastases Phase II study of pembrolizumab (10 mg/kg q2w) in patients with brain metastasis NC Metastatic melanoma (n = 18) - PD-L1+ (5%) NSCLC (n = 18) - At least 1 asymptomatic 5-20 mm brain metastasis not requiring immediate local therapy or systemic steroids Results - 18 NSCLC-evaluable patients: 33% CNS response rate (6/18, 95% CI: 14%-59%) - 18 melanoma-evaluable patients: 22% CNS response rate (4/18, 95% CI: 7%-14%) - Ongoing response in the brain in 17/18 NSCLC patients, 18/18 melanoma patients Conclusion - Blockade of the PD-1/PD-L1 pathway may confer clinical benefit in patients with PD-L1+ NSCLC with brain metastases Goldberg SB, et al. Lancet Oncol. 2016;17(7):

43 Special Patient Populations EGFR/ALK+ NSCLC A 71-year-old Asian woman with metastatic EGFR-mutant (exon19del) lung adenocarcinoma is treated with first-line erlotinib with clinical response lasting for 2 years. She develops new sites of metastatic disease that are biopsied and found to be 790M- and PD-L1 0% (22C3). What treatment approach may be suitable for this patient and why? A. Systemic chemotherapy, since the tumor is PD-L1- B. Systemic chemotherapy, since the tumor is PD-L1-, 790M- C. Osimertinib D. Systemic chemotherapy, since the tumor is PD-L1- and 790M-, and anti-pd-1/pd-l1 may be less efficacious in this subset of patients E. Afatinib

44 Anti-PD-1/PD-L1 in EGFR-Mutant NSCLC Light ( 10 pack-years) Gainor JF, et al. Clin Cancer Res. 2016;22(18):

45 Anti-PD-1/PD-L1 in EGFR-Mutant NSCLC ORR by Mutation Status PFS by Mutation Status Poor ORR; short PFS with anti-pd-1/pd-l1 in EGFR-mutant NSCLC; KI may change PD-L1 status Gainor JF, et al. Clin Cancer Res. 2016;22(18):

46 Immunotherapy in NSCLC Outline Brief Introduction to Cancer Immunotherapy A Newly Diagnosed Patient with NSCLC Diagnostic Evaluation Choice of reatment How to Manage the Patient Receiving Immunotherapy Special Patient Populations Previous Autoimmune Conditions Brain Metastases Patients With Oncogene-Driven NSCLC

47 What do you consider to be the ideal place for PD-1/PD-L1 inhibitors in NSCLC? 1. First line in combination with chemotherapy in patients without targetable mutations 2. First-line monotherapy in patients without targetable mutations 3. First line in combination with CLA-4 inhibitors in patients without targetable mutations 4. Second-line therapy (regardless of mutation status) 5. In combination with targeted therapy (either first line or second line) 6. After all other treatment options have been exhausted

48 Immunotherapy in NSCLC Unanswered questions What do we do with PD-L1 negative (<49%) patients first-line? How long do we treat patients for with anti-pd-1/pd-l1? Do we continue to exclude NSCLC patients with mild autoimmune conditions/who were previously excluded from these studies? Is the PD-L1 assay here to stay? Or will there be better biomarkers with which to select patients for immunotherapy? If so, which ones?