Inmunoterapia en el carcinoma de Células de Merkel. Jaume Capdevila Hospital Universitari Vall d Hebron Barcelona

Size: px

Start display at page:

Download "Inmunoterapia en el carcinoma de Células de Merkel. Jaume Capdevila Hospital Universitari Vall d Hebron Barcelona"

Harriet Baldwin
5 years ago
Views:

1 Inmunoterapia en el carcinoma de Células de Merkel Jaume Capdevila Hospital Universitari Vall d Hebron Barcelona

2 Epidemiology Merkel cell carcinoma is an uncommon neuroendocrine carcinoma that mostly arises in sun exposed areas, with the head and neck being the most frequent site. There is geographic variation in incidence: 2/10 6 /y EU vs 8-10/10 6 /y US & Australia It predominantly occurs in patients who are older, with onset occurring at a median age of 75 to 80, and it is more common in males. Recognized risk factors are ultraviolet sunlight exposure and immunosuppression, and more recently, the Merkel polyomavirus has been identified as a causative agent. Albores-Saavedra J, et al. J Cutan Pathol. 2010

3 FEATURES OF MCC Firm, red to purple papule/nodule Asymptomatic/lack of tenderness Rapidly expanding Metastasizes at an early stage COMMONLY AFFECTED AREAS Head and neck (~50%) Upper extremities (~16%) Lower extremities (~30%) Trunk (<5%) Prieto I, et al. Crit Review Oncol Hematol 2016

4 Wang TS, et al. Semin Cutan Med Surg 2011

5 Pathology report

6 MCPyV p53 Church, et al. J Invest Derm 2015 Feng H, et al. Science 2008

7 Mutation load Harms PW, et al. Cancer Res 2015

8 PD-1 / PD-L1 expression Afanasiev OK, et al. Clin Cancer Res 2013

MDT management No lymph-node spread Lymph-node spread Extra-nodal

adjuvant radiotherapy Surgery + radiotherapy Complete removal of satellite

established curative treatment Sentinel lymph-node biopsy is recommended

sentinel lymph node biopsy not possible, regional follow-up with

possible Elderly patients with poor performance status not suitable for

chemotherapy if surgery not feasible Electrochemotherapy possible for

limbs: isolated limb perfusion with tumor necrosis factor and melphalan,

9 MDT management No lymph-node spread Lymph-node spread Extra-nodal locoregional disease Metastatic disease Excision (1 2 cm margin) + adjuvant radiotherapy Surgery + radiotherapy Complete removal of satellite or in-transit metastases around the primary site if possible No established curative treatment Sentinel lymph-node biopsy is recommended if possible If micro-metastasis: therapeutic lymph-node dissection If sentinel lymph node biopsy not possible, regional follow-up with ultrasound every 4 months Adjuvant immunotherapy clinical trial if possible Elderly patients with poor performance status not suitable for surgery: possible radiotherapy of tumors and lymph node Radiotherapy + chemotherapy if surgery not feasible Electrochemotherapy possible for locally advanced lesions Solid tumors with locoregional diffusion on limbs: isolated limb perfusion with tumor necrosis factor and melphalan, or isolated limb infusion Mono- and polychemotherapy may be used; enrollment in a clinical trial is preferred Lebbe C et al. Eur J Cancer 2015

10 Chemotherapy Becker JC, et al. Oncotarget 2017

11 Chemotherapy First-line Second-line Becker JC, et al. Oncotarget 2017

12 Chemotherapy Becker JC, et al. Oncotarget 2017

13 Immunotherapy Patnaik A, et al. Clin Cancer Res 2015

Pembrolizumab Phase II, non-controlled, single arm Patients with advanced MCC (N = 26) No prior antitumour therapy was allowed WHO PS 1 Correlation with MCPyV: Serologic IHC I N C L U S I O N

14 Pembrolizumab Phase II, non-controlled, single arm Patients with advanced MCC (N = 26) No prior antitumour therapy was allowed WHO PS 1 Correlation with MCPyV: Serologic IHC I N C L U S I O N PEMBROLIZUMAB 2MG/KG EVERY 3 WEEKS Multiphasic CT or MRI performed every 9-12 weeks Treatment until disease progression, complete response, 2-y on therapy or toxic effects Primary Endpoint: Overall response rate by RECIST v 1.1 Secondary Endpoints: PFS, duration of response, correlation with PD-L1, MCPyV status Nghiem PT, et al. N Engl J Med 2016

15 Pembrolizumab CR: 4 pts RR MCPyV +: 62% RR MCPyV-: 44% RR: 56% Nghiem PT, et al. N Engl J Med 2016

16 Pembrolizumab mpfs: 9m Nghiem PT, et al. N Engl J Med 2016

AVELUMAB: JAVELIN 200 Merkel Trial N=200 (estimated) A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C) in subjects with Merkel cell

17 AVELUMAB: JAVELIN 200 Merkel Trial N=200 (estimated) A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB C) in subjects with Merkel cell carcinoma Patients with Histologically-proven mmcc ECOG PS 0 1 Part A: patients have received at least one line of chemotherapy (n=88) 2 Part B: patients have not received any prior systemic treatment for mmcc (n=112) 3 Tumor assessments every 6 weeks (RECIST v1.1; IERC) Avelumab 10 mg/kg IV (1-h infusion) every 2 weeks until disease progression, clinical deterioration, unacceptable toxicity or other criterion for withdrawal Part A: PRIMARY ENDPOINT: Confirmed BOR SECONDARY ENDPOINTS: DoR, PFS, OS, safety, anti-drug antibodies, PK Part B: PRIMARY ENDPOINT: Durable response SECONDARY ENDPOINTS: BOR, DoR, PFS, OS, safety, anti-drug antibodies, PK Estimated primary completion dates: Part A, complete; 2 Part B, September NCT Available at ClinicalTrials.gov (accessed October 2017). 2. Kaufman HL et al. Lancet Oncol 2016;17: ; 3. D angelo SP, et al. JAMA Oncology 2018

AVELUMAB: JAVELIN 200 Merkel Trial PART A n=88 A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C) in subjects with Merkel cell

18 AVELUMAB: JAVELIN 200 Merkel Trial PART A n=88 A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB C) in subjects with Merkel cell carcinoma Tumor assessments every 6 weeks (RECIST v1.1; IERC) Patients with Histologicallyproven mmcc ECOG PS 0 1 Received at least one line of chemotherapy for mmcc Avelumab 10 mg/kg IV (1-h infusion) every 2 weeks until disease progression, clinical deterioration, unacceptable toxicity or other criterion for withdrawal PRIMARY ENDPOINT: Confirmed BOR* SECONDARY ENDPOINTS: DoR, PFS, OS, safety, anti-drug antibodies, PK Estimated primary completion date: study complete 2 Primary analysis cut-off (patients with 6 months follow up): March 3, Final analysis cut-off (patients with 1 year follow up): September 3, *Best Overall Response is defined as complete response, partial response, stable disease, or progressive disease, according to RECIST version 1.1 and assessed by an independent review committee NCT Available at ClinicalTrials.gov (accessed July 2017). 2. Kaufman HL et al. Lancet Oncol 2016;17: Kaufman HL et al. AACR Abstract CT079 (presentation).

19 AVELUMAB: JAVELIN 200 Merkel Trial PART A Kaufman H et al. Lancet Oncol 2016

20 AVELUMAB: JAVELIN 200 Merkel Trial PART A Response (N=88) Primary results 2 ( 6 months follow up) 1 year follow up 1 ORR, % (95% CI) 31.8 ( ) 33.0 ( ) Confirmed BOR, n (%) CR PR SD PD Non-CR/non-PD Not evaluable 8 (9.1) 20 (22.7) 9 (10.2) 32 (36.4) 1 (1.1)* 18 (20.5) 10 (11.4) 19 (21.6) 9 (10.2) 32 (36.4) 0 18 (20.5) Response durability n=28 n=29 Median DOR, months (95% CI) Range NE (8.3, ) NE (18.0, ) month DRR, % (95% CI) 29.1 ( ) 30.6 ( ) Proportion in response at 1 year, % (95% CI) N/A 23.9 ( ) Responses with 6-month duration, % (95% CI) 92 (70 98) 93 (74 98) Responses with 1-year duration, % (95% CI) N/A 74 (53 87) *One patient did not have measurable disease at baseline; thus, a BOR of PR or SD could not be distinguished; ORR multiplied by Kaplan Meier estimate for 6-month proportion of DOR; crude proportion in 1-year analysis is 28.4% (19.3%, 39.0%); Based on Kaplan Meier estimates. 1. Kaufman HL et al. AACR Abstract CT079 (presentation). Data cut-off September 3, Kaufman HL et al. Lancet Oncol 2016;17: Data cut-off March 3, 2016.

AVELUMAB: JAVELIN 200 Merkel Trial PART A 10 patients with CR Two new CRs since primary analysis Median time to response: 6.1 weeks (range 6 36) 22/29 (75.9%) responses observed by Week 7 21/29 (72.

21 AVELUMAB: JAVELIN 200 Merkel Trial PART A 10 patients with CR Two new CRs since primary analysis Median time to response: 6.1 weeks (range 6 36) 22/29 (75.9%) responses observed by Week 7 21/29 (72.4%) responses ongoing 25 patients with DOR 6 months 13 patients with DOR 1 year *One patient did not have measurable disease at baseline; thus, a BOR of PR or SD could not be distinguished; ORR multiplied by Kaplan Meier estimate for 6-month proportion of DOR; crude proportion in 1-year analysis is 28.4% (19.3%, 39.0%); Based on Kaplan Meier estimates. 6 month data cut-off March 3, year data cut-off, September 3, Kaufman HL et al. AACR Abstract CT079 (presentation).

22 AVELUMAB: JAVELIN 200 Merkel Trial PART A Percentage change in sum of target lesion diameters from baseline over time for all assessable patients (n=65), defined as those patients with baseline tumor assessments and at least one post-baseline assessment. A patient with pseudoprogression is indicated by an asterisk. Upper dotted line represents progression at 20% and lower dotted line represents the RECIST boundary for CR or PR at 30%. Data cut-off March 3, Kaufman HL et al. Lancet Oncol 2016;17:

23 AVELUMAB: JAVELIN 200 Merkel Trial PART A Tumor regression from baseline as measured by RECIST v1.1 in all assessable patients (n=65) Tumor regression by 30% occurred in 29 (33%) of 88 patients Includes one patient for whom early PD by RECIST v1.1 was followed by tumor shrinkage Plot of tumor regression from baseline as measured by RECIST v1.1 in all assessable patients (n=65). Upper dotted line represents progression at 20% and lower dotted line represents the RECIST boundary for CR or PR at 30%. Data cut-off March 3, Kaufman HL et al. Lancet Oncol 2016;17:

24 PFS (%) MERKEL CELL CARCINOMA AVELUMAB: JAVELIN 200 Merkel Trial PART A PFS n=88 Events, n (%) 55 (62.5) 1-year rate, % (95% CI) 30 (21 41) Median PFS, months (95% CI) 2.7 ( ) Number at risk Months from start of systemic therapy Chemotherapy median PFS months reported in retrospective observational analyses 2 4 Avelumab 1 Cowey Becker Iyer *Figure for illustrative purposes only and is not a direct head-to-head comparison. 1. Kaufman HL et al. AACR Abstract CT079 (presentation). Data cut-off September 3, 2016; 2. Cowey CL et al. Future Oncol Epub ahead of print. doi: /fon ; 3. Becker J et al. Ann Oncol 2016;27(Suppl.):Abstract 1154P; 4. Iyer JG et al. Cancer Med 2016;5:

25 OS (%) MERKEL CELL CARCINOMA AVELUMAB: JAVELIN 200 Merkel Trial PART A Number at risk OS n=88 Events, n (%) 48 (54.5) Median, months (95% CI) 12.9 (7.5, ) 1-year rate, % (95% CI) 52 (41 62) Months since initiating treatment Avelumab Data cut-off September 3, Kaufman HL et al. AACR Abstract CT079 (presentation).

26 Kaufman HL et al. Journal for Immunotherapy of Cancer 2018

primary tumor had an ongoing response <1 year (8.

27 AVELUMAB: JAVELIN 200 Merkel Trial PART A Response durability based on Kaplan Meier estimates. One patient missing information on site of primary tumor had an ongoing response <1 year (8.8+ months). Data cut-off September 3, Kaufman HL et al. AACR Abstract CT079 (presentation).

AVELUMAB: JAVELIN 200 Merkel Trial PART A Response durability based on Kaplan Meier estimates; Of three patients with a response to avelumab and negative PD-L1 expression status based on a

28 AVELUMAB: JAVELIN 200 Merkel Trial PART A Response durability based on Kaplan Meier estimates; Of three patients with a response to avelumab and negative PD-L1 expression status based on a 1% tumor-cell staining cut-off, response was ongoing and <1 year (3.9+, and months). Data cut-off September 3, Kaufman HL et al. AACR Abstract CT079 (presentation).

29 AVELUMAB: JAVELIN 200 Merkel Trial PART A D Angelo SP et al. ESMO 2017

30 AVELUMAB: JAVELIN 200 Merkel Trial PART A Adverse reactions (n=88) All grades, n (%) Grade 3/4, n (%) Immune-mediated reaction 15 (17.0) 3 (3.4) Rash 5 (5.7) 0 Hypothyroidism 4 (4.5) 1 (1.1) Diarrhea 2 (2.3) 0 Alanine aminotransferase increased 1 (1.1) 1 (1.1) Aspartate aminotransferase increased 1 (1.1) 0 Erythema 1 (1.1) 0 Hyperthyroidism 1 (1.1) 0 Pruritus 1 (1.1) 0 Maculopapular rash 1 (1.1) 0 Transaminases increased 1 (1.1) 1 (1.1) Tubulointerstitial nephritis 1 (1.1) 0 Infusion-related reaction (IRR)* 19 (21.6) 0 *IRR occurring on the day or subsequent day of infusion included events reported as IRR, drug hypersensitivity, or hypersensitivity. In addition, signs and symptoms of an IRR occurring on the same day of infusion and resolved within 2 days are included. Date of data cut-off for updated safety: June 9, Kaufman HL et al. AACR Abstract CT079 (presentation).

AVELUMAB: JAVELIN 200 Merkel Trial PART B n=112 (estimated) A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB0010718C) in subjects with Merkel

31 AVELUMAB: JAVELIN 200 Merkel Trial PART B n=112 (estimated) A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab (MSB C) in subjects with Merkel cell carcinoma Tumor assessments every 6 weeks (RECIST v1.1; IERC) Patients with Histologicallyconfirmed mmcc ECOG PS 0 1 Not received any prior treatment for mmcc Avelumab 10 mg/kg IV (1-h infusion) every 2 weeks until disease progression, unacceptable toxicity or other criterion for withdrawal PRIMARY ENDPOINT: Durable response* SECONDARY ENDPOINTS: BOR**, DoR, PFS, OS, safety and tolerability Estimated primary completion date: September *Durable response defined as proportion of patients of the total ITT population with objective response (CR or PR) according to RECIST v1.1, with a duration of at least 6 months. 1 **Best Overall Response defined as the confirmed best response (CR or PR), according to RECIST version 1.1 and assessed by an independent review committee D angelo SP, et al. JAMA Oncology 2018

32 AVELUMAB: JAVELIN 200 Merkel Trial PART B Outcomes by RECIST v1.1 per IRC Response Confirmed response in patients with 3 months of follow-up (n=29) Confirmed response in patients with 6 months of follow-up (n=14) ORR, % (95% CI) 62.1 ( ) 71.4 ( ) BOR, n (%) Complete response Partial response Stable disease Progressive disease Non-evaluable* 4 (13.8) 14 (48.3) 3 (10.3) 7 (24.1) 1 (3.4) 4 (28.6) 6 (42.9) 1 (7.1) 2 (14.3) 1 (7.1) Response durability n=18 n=10 Median DOR, months (95% CI) NE (4.0 NE) NE (4.0 NE) Responses with 3 months duration, % (95% CI) 93 (61 99) 100 (NE NE) Responses with 6 months duration, % (95% CI) 83 (46 96) 89 (43 98) Confirmed response was defined as response criteria met again in repeat assessment performed 5 weeks after initial documentation. *Died prior to tumor assessment Data cut-off March 24, D angelo SP, et al. JAMA Oncology 2018

33 AVELUMAB: JAVELIN 200 Merkel Trial PART B D angelo SP, et al. JAMA Oncology 2018

34 AVELUMAB: JAVELIN 200 Merkel Trial PART B Adverse event (any grade 7.5% or any grade 3) Any grade, n (%) Grade 3, n (%) Any TRAE 28 (71.8) 8 (20.5) Fatigue 9 (23.1) 0 Infusion-related reactions 9 (23.1) 1 (2.6) Asthenia 3 (7.7) 0 Lipase increased 3 (7.7) 1 (2.6) Elevated ALT 3 (7.7) 1 (2.6) Blood CPK increased 2 (5.1) 1 (2.6) Autoimmune nephritis 1 (2.6) 1 (2.6) Cholangitis 1 (2.6) 1 (2.6) Elevated AST 1 (2.6) 1 (2.6) Gait disturbance 1 (2.6) 1 (2.6) Paraneoplastic encephalomyelitis 1 (2.6) 1 (2.6) Polyneuropathy in malignant disease 1 (2.6) 1 (2.6) Paraneoplastic syndrome 1 (2.6) 1 (2.6) Troponin increased 1 (2.6) 1 (2.6) D angelo SP, et al. JAMA Oncology 2018

35 Take home messages Chemotherapy (CDDP-VP16) can show responses of very short duration in advanced disease with no role in adjuvant therapy and concerns about toxicity and target patients Heterogeneity is relevant: characteristics of high & low NET grade, MCPyV +/-, high & low mutational load but all features suggest a possible benefit of immune check-point inhibitors Avelumab has demonstrated significant activity (ORR & prolonged responses) in all subgroups of patients Activity of Avelumab seams to be higher in first than in second-line. Joining the meaningful benefit and the safety profile compared with chemotherapy, Avelumab should be considered as first-line therapy in Merkel Cell carcinoma patients

36 GRACIAS POR VUESTRA ATENCIÓN

Evan J. Lipson, M.D.

Update on treatment for Merkel cell, cutaneous squamous cell and basal cell cancers Evan J. Lipson, M.D. The Johns Hopkins University School of Medicine Bloomberg~Kimmel Institute for Cancer Immunotherapy