CASE-BASED MANAGEMENT IN IMMUNO- ONCOLOGY

Transcription

1 CASE-BASED MANAGEMENT IN IMMUNO- ONCOLOGY Prof. Solange Peters, MD-PhD Cheffe de Service Oncologie Médicale & Clinique Thoracique CHUV- Lausanne & Institut Ludwig

2 GENERAL QUESTIONS Your 62-yr-old patient, a former smoker, was diagnosed with metastatic adenocarcinoma NSCLC Negative for EGFR mutation and ALK translocation After 4 cycles of carboplatin/pemetrexed, restaging scans showed new lung and bone lesions and increasing lymphadenopathy When discussing new treatment options, he asks about his chances of being alive after 1 year or 2 years on a checkpoint inhibitor

3 What would you tell your patient regarding the risk of death with PD-1 inhibitors? 1. Approximately 20% of similar patients receiving PD-1 inhibitors are still alive at 1 year 2. Approximately 50% of similar patients receiving PD-1 inhibitors are still alive at 1 year 3. Approximately 75% of similar patients receiving PD-1 inhibitors are still alive at 1 year 4. Over 90% of similar patients receiving PD-1 inhibitors are still alive at 1 year 5. Unsure

4 What is the minimum level of PD-L1 expression by IHC needed for you to prescribe pembrolizumab for a patient with NSCLC? 1. 1% 2. 10% 3. 25% 4. 50% 5. Any patient 6. Unsure

5 For which of the following patients would you assess PD-L1 expression when considering treatment with PD-1 inhibitors? 1. Any patient with advanced NSCLC frontline 2. A current smoker with advanced adeno NSCLC and no know genetic aberrations 3. All patients in any line of treatment 4. A patient with advanced EGFR-positive NSCLC 5. Unsure

6 HOW GOOD ARE WE IN PREDICTING BENEFIT?

7 Ms. W. 1949, tumor immunogenicity 63 yo, non-smoking, Caucasian : Lung adenocarcinoma of the right lower lobe, ct2b cn2 cm0, IIIA

8 Ms. W. 1949, tumor immunogenicity SAKK-16/00: - neo-adjuvant chemotherapy with cisplatin-docetaxel - thoracic radiotherapy - surgery (lobectomy and mediastinal lymph node dissection)

9 Ms. W. 1949, tumor immunogenicity : Good partial response after chemo- and radiotherapy : Surgery => complete resection: ypt2b ypn0, R0

10 Ms. W. 1949, tumor immunogenicity 8 months later : bilateral lung metastases Molecular testing: HER2 mutation (exon 20 insertion)

11 Ms. W. 1949, tumor immunogenicity Molecular testing: HER2 mutation (exon 20 insertion) => No study for HER2 mutation at our center in : 1 st line cisplatin-pemetrexed => PR : pemetrexed maintenance => lung PD : 2 nd line taxane-trastuzumab => PR : trastuzumab maintenance => lung PD : 3 rd line afatinib => lung PD : 4 th line carboplatin-vinorelbine-trastuzumab => lung PD : 5 th line gemcitabine-trastuzumab => lung PD

12 Ms. W. 1949, tumor immunogenicity 6 th line nivolumab => PR! -> Lasting > 9 months CR in March 2018 Of note: PD-L1 negative One case study of response to nivolumab in PD-L1 positive HER2 mutant (Catania, CLC 2016)

13 Lung cancer facts Lung cancer is characterized by a strongly immunosuppressive environment We have been enrolling thousands of patients in strictly negative vaccine trials Lung tumors display ~200 nonsynonymous mutations per tumor. Lung cancers from smokers have 10 times as many somatic mutations as those from non smokers. Vogelstein, Science 2013 Lawrence, Nature 2013

14 Mutational smoking signature Physicochemical properties of the mutagen determine which adduct is formed, what repair mechanism is induced and which mispairing is permissible Fingerprint mutation due to tobacco exposure is a C A transversion, which is predominantly found in smokers Jia et al. BMC Medical Genomics 2014

15 High mutation load in NSCLC Huge variation across cancer types 1000-fold! Lawrence M et al. Nature 2013

16 Mutation frequency varied markedly across patients within a cancer type Lawrence M et al. Nature 2013

17 Some complexity in PD-L1 Diagnostics for NSCLC Nivolumab: BMS Pembrolizumab: Merck Atezolizumab: Roche Durvalumab: AstraZeneca Avelumab: Pfizer Ab Clone 28-8 SP263 22C3 SP142 SP Diagnostic Partner Dako Ventana Dako Ventana Ventana Dako Scoring Method Diagnostic Status Approved IVD PD-L1 Threshold PD-L1 Thresholds % of PD-L1 expressing tumour cells Complementary: testing not required US/EU: NSQ NSCLC US/EU: All patients eligible EU: NSQ NSCLC EU: All patients eligible 1% (pos), 5% (strong), or 10% Validated % of PD-L1 expressing tumour cells Companion: testing required US/EU: SQ and NSQ NSCLC US: 50% EU: 1% 1% (pos) 50% (strong) Validated % of PD-L1 expressing tumour cells or immune cells Dx not approved for NSCLC setting % of PD-L1 expressing tumour cells Dx not approved for durvalumab in any setting % of PD-L1 expressing tumour cells Dx not approved for avellumab in any setting NA NA NA TC / IC 3(+) TC / IC 2(+) TC / IC 1(+) TC / IC 0( ) TC PD-L1(+): 25% TBC, TC between all >1% and 25% with moderate or high intensity

18 Tumor Mutation Burden (TMB) as a Predictive Biomarker for Immuno-Oncology Agents 1.Snyder A et al. N Engl J Med 2014;371: Rizvi NA et al. Science 2015;348: Hellmann M. Presented at the 14th International Congress on Targeted Anticancer Therapies; March 21 23, 2016; Washington, DC, USA. Oral O2.2 18

19 P e rc e n t p ro g re s s io n -fre e Highly significant correlation between non-synonymous mutation burden and durable pembrolizumab benefit A ll s e q u e n c e d tu m o r s 91% durable benefit (partial or stable H ig h n o n s y n o n y m o u s b u rd e n response Llasting o w n o n s y>6 n o n ymonths) o u s b u rd ein n high mutation burden and any level of PD-L1 expression M o n th s High nonsynonymous burden (n=17) Low nonsynonymous burden (n=17) Rizvi N, et al. Science. 2015;348(6230):

20 S A Y e s H E Y e s T U N o Y Y e s M Y e s R I Y e s ZA N o C U N R C A Y e s S C Y e s F R N R K A Y e s M A N o ZA N R AL Y e s J B N o S R N o D I Y e s S B Y e s R H Y e s S C Y e s B L N o G R N o D M N o R _ 2 N o W A N o R O N o L O N o L O N o G R Y e s V A N o N I N o AU N o V A N o T o ta l s o m a tic e x o n ic b u rd e n Some highly mutated tumors do not respond DCB NDB NR 378 Nonsynonymous 292 Durable clinical benefit* (n=14) No durable Benefit (n=17) Rizvi N, et al. Science. 2015;348(6230):

21 ORR (%) Borghaei et al NEJM % 15% 11% Efficacy in EGFR subgroups Atezolizumab Docetaxel 14% Lack of improved efficacy relative to docetaxel in EGFR M+ 13% Mutant Wild type OS HR PFS HR ITT % n = Hazard Ratio In favor of atezolizumab In favor of docetaxel Mutant Wild type ITT

22 Tumor and Immune-Based Biomarkers Being Evaluated to Predict Better Outcomes to Immuno-Oncology Therapy Tumor antigens (eg, tumor mutation burden) Tumor immune suppression (eg, PD-L1 & other checkpoints) Host Inflamed tumor (eg, gene signatures, TILs, & TAICs) (eg, microbiome & SNPs) 1.Blank CU et al. Science 2016;352:

23 HOW TO MANAGE TOXICITIES?

24 Toxicities with Checkpoint Protein Inhibitors Organ-specific events Skin Gastrointestinal Liver Pulmonary Endocrine system Cardiovascular Immune-related adverse events (auto-inflammatory toxicities) Unchecked immune response General events Fatigue Pyrexia, chills Infusion reactions Immune selftolerance

25 Champiat, et al. Ann Oncol 2016 Spectrum of toxicity of checkpoint inhibitors Uveitis Conjunctivitis (Epi)scleritis Myocarditis Pericarditis Vasculitis Hepatitis Colitis Ileitis Pancreatitis Gastritis Arthritis Dermatomyositis Haemolytic anaemia Thrombocytopenia Blepharitis Retinitis Neutropenia Haemophilia Eye Cardiovascular Liver Gastrointestinal Musculoskeletal Blood Neurological Endocrine Respiratory Renal Skin Neuropathy Guillain-Barré Myelopathy Hyper-/hypothyroidism Hypophysitis Adrenal insufficiency Diabetes Pneumonitis Pleuritis Sarcoid-like granulomatosis Nephritis Rash Pruritus Psoriasis Meningitis Encephalitis Myasthenia Vitiligo DRESS Stevens Johnson

26 Frequently encountered toxicities

27 Severe AEs: the 1-5% toxicities CheckMate 017 (n=131) All Grade Grade 3 4 CheckMate 057 (n=287) All Grade Grade 3 4 KEYNOTE-010 (2mg/kg arm) (n=339) All Grade Incidence 5% Incidence 2 4% Incidence 1% Grade 3 4 All Grade OAK (n=609) Grade 3 4 Pneumonitis 5% 1% 3% 1% 5% 2% 1% <1% Hypothyroidism 4% 0% 7% 0% 8% 0% NR NR Hyperthyroidism NR NR 1% 0% 4% 0% NR NR Hepatitis NR NR NR NR <1% <1% <1% <1% Colitis 1% 1% 1% <1% 1% 1% <1% 0%

28 Principles of management of Immune-Related Adverse Events Grade Steroids Study Treatment Persistent/ Recurring Treat symptomatically; No systemic steroids Steroids for selected iraes and for recurrent iraes Systemic Steroids, prolonged tapers 4 Systemic steroids Can continue Continue Hold for selected AEs* Withhold or discontinue 1 Discontinue (unless endocrine irae) Systemic steroids; Consider withholding; discontinue if 12 weeks Systemic steroids and discontinue Add other immune suppressants Selected AEs: colitis, pneumonitis, liver/renal toxicity, hypophysitis, neurologic Systemic steroids (PO or IV): 1 2 mg/kg/d prednisone or equivalent Slow taper over 4 weeks is recommended. Several courses may be necessary if symptoms worsen when dose decreased. *Discontinue for G3/4 iraes renal toxicity, pneumonitis and infusion reactions; question for liver grade 3.

29 Medical history Female, 65 years old 40 pack-year smoking history 2011: diagnosis NSCLC with pulmonary and peritoneal metastasis Diagnosis Squamous cell carcinoma Stage IIIA (T1N2M0) Right hilar primary Mediastinal lymphadenopathy CZ/TCN/1117/0023

30 Initial treatment 2011: concurrent chemo-radiotherapy 2015: relapsed disease First-line treatment Right hilum, mediastinal lymphadenopathy, right effusion Treatment after first relapse 2015: Gemcitabine/carboplatin Partial response CZ/TCN/1117/0023

31 Disease progression May 2016: second relapse Progressive right hilar disease Immunotherapy initiated Unknown PD-L1 status Insufficient tissue for testing June 2016: nivolumab started CZ/TCN/1117/0023

32 September 2016: adverse event Cycle 4 (Aug 2016) Improvement in pain, fatigue and dysphagia Partial response Cycle 6 (Sep 2016) Dyspnoea, cough (no sputum) Mild fever: 37.7 C Oxygen saturation 95% (RA) WCC = 5.7 x 10 9 /L ANC = 3.4 x 10 9 /L CRP = 23mg/L CZ/TCN/1117/0023

33 September 2016: after 6 cycles of nivolumab CZ/TCN/1117/0023

34 What grade of pneumonitis? Grade Symptoms Asymptomatic Clinical or diagnostic observations only Intervention not indicated Symptomatic Medical intervention indicated Limiting instrumental ADL Severe symptoms Limiting self care ADL Oxygen indicated Life-threatening respiratory compromise Urgent intervention indicated (e.g. tracheotomy or intubation) Death

35 If you were treating this patient, what would you do? 1. Oral antibiotics, continue immunotherapy 2. Oral corticosteroids, continue immunotherapy 3. Stop immunotherapy, bronchoscopy and lavage 4. Stop immunotherapy, start oral corticosteroids 5. Admit to hospital, permanently discontinue immunotherapy

36 Initial actions Nivolumab paused Prednisolone (1mg/kg) Weaning 5mg per week Additional omeprazole, alendronate and calcium supplements Empiric oral co-amoxyclav AE management strategy Case review Case discussed in lung cancer MDT Respiratory review Biopsy / bronchoscopy not considered necessary Weekly to 2-weekly review CT scan repeated after 6 weeks

37 Repeat CT scan (after 6 weeks) CZ/TCN/1117/0023

38 What is the median time to onset of 1. 2 weeks 2. 1 month 3. 2 months 4. 4 months 5. 6 months pneumonitis?

39 Pneumonitis More frequent in NSCLC (5 8%) than melanoma (2%) Cough, dyspnoea, LRTI Median time: onset 2.1 months, resolution 1.4 months Toxicity severity Adapted from Weber, et al. J Clin Oncol 2012; Weber, et al, J Clin Oncol Time (weeks) Rash, pruritus Diarrhoea, colitis Hypophysitis Liver toxicity

40 22% Naidoo, et al. J Clin Oncol 2017 Pneumonitis with PD-1/PD-L1 inhibitor 15% 7% 19% 37% Chronic obstructive pneumonia Ground-glass opacities Hypersensitivity Interstitial Not otherwise specified

41 Pulmonary irae Ipilimumab Nivolumab Nivolumab Oncology (Williston Park) Nov;28 Suppl 3:30-8.

42 Grade Management guidelines for pneumonitis 1. Asymptomatic 2. Symptomatic, limiting ADLs 3. Symptomatic, limiting self-care ADLs 4. Life threatening Management guidelines Hold immunotherapy Steroids (e.g. prednisone 1mg/kg/day or equivalent) Re-assess 3 weeks: continue treatment if completely resolved As for G1 plus: Consider admission Prednisone 1 2mg/kg/day PO or equivalent Empiric antibiotics if suspicious for concurrent infection Reassess every 1 3 days If improving taper steroids, continue treatment if symptoms resolve Discontinue immunotherapy permanently Hospitalise High-dose steroids (methylprednisolone 1g/day IV) Prophylactic antibiotics Consider bronchoscopy with biopsy Re-assess daily If not improving after 48h or worsening, consider infliximab, mycophenylate, or immunoglobulins If improving, taper steroids As for G3 plus: Intensive care input

43 Pneumonitis Case study cont d: outcome Initial symptomatic improvement Complicated by intercurrent lower respiratory tract infection Steroids tapered off over 8-week period Nivolumab restarted Oct 2016 Initial stable disease Clinical progression and performance status declined Dec 2016: nivolumab discontinued Feb 2017: patient died

44 AE management: clinical scenario 1 57-year-old male patient Treatment history Presentation after 10 weeks on therapy Metastatic non-squamous NSCLC; no driver mutations PD-L1 negative First-line cisplatin/pemetrexed x6 Disease progression within 9 months Started second-line IO (anti-pd(l)-1) Grade 2 skin rash Grade 1 pruritus

45 1. Continue IO; monitor patient What would you do next? 2. Continue io; start topical emollients and mild-strength corticosteroid creams 3. Continue IO; start topical emollients and mild-strength corticosteroid creams; start antihistamines 4. Temporarily stop IO; start topical emollients and mild-strength corticosteroid creams; start antihistamines 5. Permanently discontinue IO; start topical emollients and high-strength corticosteroid creams; start antihistamines

46 Cancer immunotherapy Treatment Follow-up Haanen, et al. Ann Oncol 2017 Immune-related rash Grade 1 2 Continue (at least 1 week) Start topical emollients, antihistamines in the case of pruritus and/or topical (mild strength) corticosteroid creams Reinitiate cancer immunotherapy when Grade 1 Grade 3 Interrupt Start immediate treatment with topical emollients, antihistamines and high-strength corticosteroid creams Reinitiate cancer immunotherapy when rash is resolved Grade 4 Permanently discontinue Seek urgent dermatology review; start i.v. corticosteroids [1 2mg/kg (methyl)prednisolone] Taper based on response of AE

47 Cutaneous irae

48 Cutaneous irae Erythematous papilles, confluent plaques, predominantly in regions with fine skin Eczema

49 Cutaneous irae

50 Cutaneous irae

51 Cutaneous irae

52 AE management: clinical scenario 2 54-year-old female patient Treatment history Presentation after 3 weeks on therapy T3, triiodothyronine; T4, thyroxine Metastatic NSCLC (adenocarcinoma) First-line carboplatin/paclitaxel + Avastin x6 Disease progression within 12 months Started second-line IO Routine thyroid-stimulating hormone (TSH) returns low Heart rate in clinic is 100 with intermittent palpitations You order additional lab tests, which reveal: Lab Value Normal range TSH (MIU/L) Free T4 (ng/dl) Free T3 (pg/dl) Thyroglobulin Ab (IU/mL)

53 What would you do next? 1. Continue IO; initiate antithyroid medication; repeat labs in 3 days 2. Continue IO; initiate steroids; repeat labs in 3 days 3. Temporarily stop IO; initiate antithyroid medication; repeat labs in 3 days 4. Temporarily stop IO; initiate steroids; repeat labs in 3 days 5. Permanently discontinue IO; monitor patient

54 IO Treatment Follow-up Immune-related hyperthyroidism and hypothyroidism Symptomatic hyperthyroidism Interrupt Start symptomatic therapy including antithyroid medicinal product as needed; evaluate TSH and free T3/T4 every 3 5 days Restart IO when asymptomatic; if no improvement, permanently discontinue IO and refer to an endocrinologist Hyperthyroidism symptoms Anxiety, fatigue, sleep problems, heart palpitations, hand tremors, skin dryness Hypothyroidism symptoms Headaches, fatigue, weight loss, weight gain, change in mood, hair loss, constipation Symptomatic hypothyroidism Interrupt Start hormone replacement therapy; TSH and clinical evaluation every 3 5 days Restart IO when asymptomatic and TSH levels are decreasing; if no improvement, permanently discontinue IO and refer to an endocrinologist

55 Endocrine irae

56 AE management: clinical scenario 3 67-year-old male patient Treatment history Presentation after 4 weeks on therapy Case adapted from Li, et al. J Hematol Oncol 2017 Metastatic squamous NSCLC Adjuvant chemotherapy and radiation Following progression, enrolled on clinical trial and received docetaxel + investigational agent Following progression, started third-line IO Dyspnoea and fatigue Grade 3 pneumonitis at week 6

57 What would you do next? 1. Continue IO; monitor patient 2. Continue IO; start prednisone 3. Temporarily stop IO; provide oxygen; start prednisone 4. Permanently discontinue IO; provide oxygen; start prednisone

58 IO Treatment Follow-up Immune-related pneumonitis Grade 2 Interrupt Monitor daily; consider bronchoscopy and lung biopsy; start 1 2mg/kg/day prednisone or equivalent Reassess every 1 2 weeks: resume IO if Grade 1 within 12 weeks; treat as Grade 3 4 if no improvement Symptoms New or worsening cough, shortness of breath and chest pain Grade 3 4 Permanently discontinue Provide O 2 ; monitor daily; consider bronchoscopy and lung biopsy; start 1 2mg/kg/day prednisone or equivalent Reassess every 3 5 days: if no improvement after 48h, consider additional immunosuppressant and refer to a pulmonologist

59 AE management: clinical scenario 4 60-year-old female patient Treatment history Presentation after 20 weeks on therapy Metastatic squamous NSCLC First-line cisplatin/gemcitabine x6 Disease progression within 6 months Started second-line IO Grade 2 fatigue Grade 2 diarrhoea (six bowel movements/day over last 5 days) Crampy abdominal pain Blood tests indicate Grade 2 acute kidney injury

60 1. Continue IO; monitor patient What would you do next? 2. Continue IO; start i.v. fluids and steroids 3. Temporarily stop IO; start i.v. fluids and steroids 4. Permanently discontinue IO; monitor patient

61 IO Treatment Follow-up Grade 2 Interrupt if persists for >5 days or recurs Initiate symptomatic treatment and monitor every 2 3 days; if persists for >5 days, treat with 1 2mg/kg/day prednisone or equivalent Reassess weekly: resume IO if Grade 1 within 12 weeks; treat as Grade 3 4 if no improvement Immune-related colitis Grade 3 Interrupt Initiate symptomatic treatment and monitor daily; treat with 1 2mg/kg/day i.v. (methyl)prednisolone or equivalent, followed by 1 2mg/kg/day prednisone or equivalent upon improvement Reassess every 3 5 days: resume IO if Grade 1 within 12 weeks; treat as Grade 4 if no improvement Symptoms Diarrhoea, blood in stool and pain in stomach area Grade 4 Permanently discontinue Initiate symptomatic treatment and monitor daily; consider endoscopy with biopsy; treat with 1 2mg/kg/day i.v. (methyl)prednisolone or equivalent, followed by 1 2mg/kg/day prednisone or equivalent upon improvement Reassess every 1 3 days; taper corticosteroids if Grade 1; consider additional immunosuppressant and refer to a gastroenterologist

62 Colonic irae: endoscopy showing deep ulcers

63 Colonic irae: histoligical signs of colonic inflammation Berman D et al. Cancer Immunity 2010; 10:11-22

64 Pet-CT)

65 REALITY OF DAILY LIFE?

66 Medical history Male, 73 years old Never smoker ECOG PS 1 No relevant comorbidities Presented with cough and bronchial haemoptysis Mr. B July 2011: diagnosis Histopathologic diagnosis Biopsy of right internal jugular lymph node Stage IVA adenocarcinoma T2a (right upper lobe 4 cm) N2 (mediastinal lymph node) M1b (right internal jugular lymph node) EGFR, ALK WT

67 Systemic treatment July October 2011 Cisplatin/pemetrexed 4 cycles: induction Partial response Mr. B First line treatment Radiotherapy November December 2011 Sequential radiotherapy: mediastinal and right cervical/supraclavicular lymph nodes January 2012 Stereotactic radiotherapy: right upper lobe follow up

68 Mr. B December 2012: CT/PET scans 11 months after sequential chemotherapy/radiotherapy

69 Mr. B May 2013: first disease progression (PET scans) May 2014: Surgery Left adrenalectomy

70 Mr. B October 2014: thoracic CT scan without disease

71 But: Presence of abdominal lymph nodes and subcutaneous tissue nodes

72 November 2014: start of atezolizumab April 2015: SD Minor AE reported Grade 1 pruritus (resolved)

73 July 2017: stable disease after three years on atezolizumab

74 Educate patients about signs of organ inflammation that require prompt referral FINAL MESSSAGE Severe loss of vision in one or both eyes Headache, confusion, muscle weakness, numbness Fatigue, weight loss, nausea, vomiting, thirst/appetite increase, polyuria Shortness of breath, coughing Diarrhoea, blood or mucus in the stool, severe abdominal pain Arthralgia or swelling joints Haemorrhagic syndrome Extensive rash, severe pruritus