WSMOS Fall meeting: Advances in the treatment of metastatic and - - PowerPoint PPT Presentation

WSMOS Fall meeting: Advances in the treatment of metastatic and high-risk melanoma

John A. Thompson MD jat@uw.edu Office: 206-288-2044

MS Lawrence et al. Nature 000, 1-5 (2013) doi:10.1038/nature12213

Somatic mutation frequencies observed in exomes from 3,083 tumour–normal pairs.

Chen DS Immunity 39:1, 2013

Mechanism ¡of ¡ac-on ¡of ¡Ipilimumab ¡and ¡Nivolumab ¡

T cell Tumor ¡cell ¡

MHC TCR PD-L1 PD-1

• - -

T cell Dendritic cell

MHC

TCR CD28 B7 CTLA-4 - - -

Activation (cytokines, lysis, proliferation, migration to tumor)

B7

+ + + + + +

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)

anti-CTLA-4 anti-PD-1

Tumor Microenvironment

+ + +

PD-L2 PD-1

anti-PD-1

• - -

Activity of Anti–Programmed Death 1 (PD-1) Antibody in Patients with Refractory Melanoma

.

Complete/partial Response (CR/PR): 33/107 (31%) Stable Disease (SD): 7/107 (7%)

Topalian SL, et al. N Engl J Med 2012;366:2443-2454. Topalian SL, et al. J Clin Oncol 2014;32:1020-1030.

Immune-related adverse experiences (irAEs) www.hcp.yervoy.com/mm/resources-library Adverse reaction management guide Patient Wallet Card Skin: § Pruritus § Rash Gastrointestinal § Diarrhea § Abdominal Pain § Blood in stool § Bowel perforation § Peritoneal signs Liver: § ↑ AST/ALT, Bili Endocrine § Fatigue § Headache § Mental status changes § Hypotension § Abnl thyroid function tests/serum chemistries Neurological § Uni- or bilateral weakness § Sensory alterations § Paresthesias

¡ ¡ ¡ CA209-­‑067 ¡Study ¡Design ¡

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Randomized, ¡double-­‑blind, ¡phase ¡III ¡study ¡ to ¡compare ¡NIVO ¡+ ¡IPI ¡or ¡NIVO ¡alone ¡ ¡to ¡IPI ¡alone ¡

Unresectable or Metatastic Melanoma

• Previously untreated
• 945 patients

Treat until progression**

• r

unacceptable toxicity NIVO 3 mg/kg Q2W + IPI-matched placebo NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo

Randomize 1:1:1 Stratify by:

• PD-L1

expression*

• BRAF status
• AJCC M stage

*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances.

N=314 N=316 N=315

¡ ¡ ¡ CA209-­‑067 ¡Study ¡PFS ¡and ¡OS ¡

CA209-­‑067 ¡Response ¡to ¡Treatment ¡ ¡ ¡ ¡ ¡ ¡

¡ ¡ ¡ ¡ ¡ ¡

CA209-­‑067 ¡Safety ¡Summary ¡

PaJents ¡ReporJng ¡Event, ¡% ¡

NIVO ¡+ ¡IPI ¡(N=313) ¡ NIVO ¡(N=313) ¡ IPI ¡(N=311) ¡

Any ¡ Grade ¡ Grade ¡ ¡ 3–4 ¡ ¡ Any ¡ Grade ¡ Grade ¡ ¡ 3–4 ¡ ¡ Any ¡ Grade ¡ Grade ¡ ¡ 3–4 ¡ ¡ Treatment-­‑related ¡adverse ¡ event ¡(AE) ¡ 96 ¡ 55 ¡ 82 ¡ 16 ¡ 86 ¡ 27 ¡ Treatment-­‑related ¡AE ¡leading ¡ to ¡disconJnuaJon ¡ ¡ 36 ¡ 29 ¡ 8 ¡ 5 ¡ 15 ¡ 13 ¡ Treatment-­‑related ¡death* ¡ ¡ 0 ¡ 0.3 ¡ 0.3 ¡

*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest)

• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-

related AEs developed a response

• NIVO alone and NIVO + IPI significantly improved PFS and ORR vs. IPI alone in

patients with previously untreated melanoma – NIVO + IPI resulted in numerically longer PFS and a higher ORR vs. NIVO alone, but these results not compared statistically

– In patients whose tumors have ≥5% PD-L1 expression, both NIVO alone and

NIVO + IPI resulted in a similar prolongation in PFS, although ORR was numerically higher with NIVO + IPI

• Based upon available evidence, the combination represents a means to improve
• utcomes vs. NIVO alone, particularly for patients whose tumors have <5% PD-

L1 expression

CA209-­‑067 ¡ ¡Conclusions ¡ ¡ ¡ ¡ ¡

CA209-­‑067 ¡PFS ¡by ¡PD-­‑L1 ¡Expression ¡Level ¡(1%) ¡ ¡ ¡ ¡ ¡ ¡

155 171 164 91 97 47 32 34 16 113 115 83 78 83 36 1 1 4 7 3

• No. at risk

NIVO + IPI NIVO IPI

3 6 9 12 15 18 21

Months

Proportion alive and progression-free

1.0 0.8 0.6 0.4 0.2 0.0

NIVO + IPI NIVO IPI

3 6 9 12 15 18

0.2 0.4 0.6 0.8 1.0 0.0

Proportion alive and progression-free

NIVO + IPI NIVO IPI 123 117 113 65 42 19 26 13 5 82 50 39 57 34 12 6 2

• No. at risk

NIVO + IPI NIVO IPI

Months *Per validated PD-L1 immunohistochemical assay with expression defined as ≥1% of tumor cells showing PD-L1 staining in a section of at least 100 evaluable tumor cells.

PD-L1 ≥1%* PD-L1 <1%*

mPFS ¡ ¡ HR ¡ ¡ NIVO + IPI 12.4 ¡ ¡ 0.44 ¡ NIVO 12.4 ¡ ¡ 0.46 ¡ ¡ IPI 3.9 ¡

• ­‑-­‑ ¡

mPFS ¡ ¡ HR ¡ ¡ NIVO + IPI 11.2 ¡ ¡ 0.38 ¡ ¡ NIVO 2.8 ¡ ¡ 0.67 ¡ IPI 2.8 ¡

• ­‑-­‑ ¡

N= 490 N= 353

Standard dose pembrolizumab + reduced dose ipilimumab for metastatic melanoma

Long GV et al Lancet Oncol 18:1202, 2017

153 Pts with metastatic melanoma Pembro 2 mg/kg + Ipi 1 mg/kg q 3 wks x 4 doses Pembro 2 mg/kg q 3 wks for up to two years or disease progression or intolerance

Standard dose pembrolizumab + reduced dose ipilimumab for metastatic melanoma

Long GV et al Lancet Oncol 18:1202, 2017

Grade 3-4 immune-related toxicity 27%

All (n=153) PDL-1 pos (n=127) PDL-1 neg (n=24) C R 23 (15%) 18 (14%) 4 (17%) PR 70 (46%) 61 (48%) 8 (33%)

Long GV et al Lancet Oncol 18:1202, 2017

Tumor Staining for PD-L1: Correlation with Response to Therapy with Anti-PD-1 or Anti-PD-L1

Topalian SL, et al. N Engl J Med 2012;366:2443-2454. Grosso J, et al. ASCO Meeting Abstracts 2013;31:3016. Herbst RS, et al. ASCO Meeting Abstracts 2013;31:3000. Robert C, et al. N Engl J Med 2015;372:320-330.

Overall Response Rate PD-L1 Positive PD-L1 Negative Topalian (NEJM 2012) 9/25 0/17 Grosso (ASCO 2013) 7/16 3/18 Herbst (ASCO 2013) 13/33 8/61 Robert (NEJM 2015) 53% 33%*

*PD-L1 negative or indeterminate

Slide 20

Presented By Michael Atkins at 2015 ASCO Annual Meeting

Hypothesis 1: Interferon-γ Response Genes Will Predict Response to Pembrolizumab

Presented By Antoni Ribas at 2015 ASCO Annual Meeting

PFS and OS in Patients With Melanoma and<br />IFNγ Signature Score Above and Below the Cutoff

Presented By Antoni Ribas at 2015 ASCO Annual Meeting

Presence of Tregs and expression of PD-L1 and IDO are associated with a CD8+ T cell infiltrate

Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Expression of differentiation antigens and cancer-germline antigens is comparable in T cell signature-high versus -low patients

Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Overall mutational load (non-synonymous mutations) is comparable in T cell signature-high versus -low samples

Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

48% of non-T cell-inflamed tumors show evidence of active b-catenin signaling, which inhibits immune cell recruitment into tumor site

Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016

Whole exome sequences from tumors from 38 pts with metastatic melanoma, and pt-matched normal tissue for germline references 21 responding pts 17 non-responding pts 14 pts with prior MAPKi therapy Median of 489 non-synonymous somatic mutations (range 73 - 3985)

High mutational loads associated with Improved survival, ….. but were not associated with response to therapy. Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016

Gene set variance analysis scores Survival of PD-1-treated pts based on presence or absence of “innate anti-PD-1 resistance” (IPRES) signature (ñ gene expression for epithelial to mesenchymal transition, angiogenesis, and wound- healing) Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016 IPRES signature was detected in residual tumor after MAPKi therapy, suggesting that induction of this signature may impair responsiveness to combined MAPKi and anti-PD-1 therapy.

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016

The virus invades both tumor cells and normal healthy cells The virus is an attenuated virus that does not replicate in healthy cells Healthy cells remain undamaged The virus invades both tumor cells and normal healthy cells The virus selectively replicates and generates GM-CSF in tumor cells Tumor cells rupture to release replicated viruses and GM-CSF; TSAs are exposed

Virus GM-CSF Granulocyte-macrophage colony-stimulating factor TSAs Tumor specific antigens Normal healthy cells Tumor cells Mature dendritic cells

GM-CSF recruits dendritic cells to tumor sites Dendritic cells process and present TSAs to mediate a tumor specific immune response Adaptive immune response identifies and destroys tumor cells systemically Replicated viruses repeat cell lysis cycle in nearby tumor cells

T-VEC (n=295) GM-CSF (n=141) p value Durable Response 48 (16%) 3 (2.1%) < 0.001 CR 32 (10.8%) 1 (<1%) PR 46 (15.6%) 7 (5%) ORR 26.4% 5.7% < 0.001

Talimogene Laherparepvec (T-VEC) Improves Durable Response Rate in Patients with Advanced Melanoma

Patients with injectable melanoma that was not surgically resectable (N=436) randomized to:

• T-VEC (n=295) intralesional injection week 0, 3, then every 2 weeks
• GM-CSF (n=141) 125 mcg/m2 SC days 1-14 every 28 days

Andtbacka RH, et al. J Clin Oncol 2015;33:2780-2788.

Outcomes in Patient Subgroups

GM-CSF, granulocyte macrophage colony-stimulating factor; T-VEC, Talimogene Laherparepvec Andtbacka RH, et al. J Clin Oncol 2015;33:2780-2788.

IIIB, IIIC, IVM1a IV M1b or IV M1c First-line therapy TVEC GM-CSF ≥2nd Line

Study Rationale<br />

Presented By Georgina Long at 2015 ASCO Annual Meeting

COMBI-d: Study Design

Presented By Georgina Long at 2015 ASCO Annual Meeting

COMBI-d: Best Confirmed Response

Presented By Georgina Long at 2015 ASCO Annual Meeting

COMBI-d: Treatment-Related Adverse Events (≥20% of Patients)

Presented By Georgina Long at 2015 ASCO Annual Meeting

Fever: Temp ≥ 38.5ºC is common (~55%) with combined BRAF and MEK inhibitors (with BRAF monotherapy ~20%). Onset often 2-4 weeks following the start of therapy Chills, night sweats, rash, dehydration, electrolyte abnormalities, and êBP. Stopping dabrafenib at the onset of pyrexia will often interrupt the episode, and treatment can be resumed with full-dose dabrafenib upon resolution of pyrexia and pyrexia-related symptoms. Upon re-exposure to dabrafenib, pyrexia events may recur, but grade >3 events are uncommon (21%). For prolonged or severe pyrexia not responsive to discontinuation of dabrafenib, prednisone (10 mg/day) may be used. Patients with pyrexia should be advised to use antipyretics as needed and increase fluid intake.

Long GV, et al. Lancet 2015;386:444-451.

Dabrafenib + Trametinib (n=211) Dabrafenib (n=212) p value Median PFS (months) 11.0 8.8 0.0004 Median OS (months) 25.1 18.7 0.0107 2-year OS 51% 42% CR 16% 13% PR 53% 40%

Long GV, et al. Lancet 2015;386:444-451.

After cessation of study treatment, 33% of patients in the dabrafenib/trametinib arm and 51% of patients in the dabrafenib arm received other treatments, most commonly ipilimumab. In the dabrafenib/trametinib group, fever and flu-like reaction were more common, but cutaneous squamous cell cancers and hyperkeratosis were less common.

June 22 , 2017 Aug 3, 2017 after one month Dab + Tram

COMBI-MB

Presented By Michael Davies at 2017 ASCO Annual Meeting

COMBI-MB: Study Design (phase 2)

Presented By Michael Davies at 2017 ASCO Annual Meeting

Intracranial Response

Presented By Michael Davies at 2017 ASCO Annual Meeting

A Randomized Phase 2 Study of Nivolumab or Nivolumab plus Ipilimumab in Patients with Melanoma Brain Metastases: <br />The Anti-PD1 Brain Collaboration (ABC) <br />

Presented By Georgina Long at 2017 ASCO Annual Meeting

Study Design

Presented By Georgina Long at 2017 ASCO Annual Meeting

Slide 11

Presented By Georgina Long at 2017 ASCO Annual Meeting

Summary

Presented By Georgina Long at 2017 ASCO Annual Meeting

Summary

Presented By Georgina Long at 2017 ASCO Annual Meeting

Treatment cessation Patient selection Treatment recommendations Diagnostic workup

Proceed with surgery § Patient and tumor data reviewed by multidisciplinary team § Staging confirmed including pathology, imaging, serum LDH, mutation analysis of tumor § Evaluation for metastasectomy § Special attention to the presence of CNS disease , tempo of disease, disease burden and clinical performance status Treatment until response, progression or unacceptable adverse effects BRAF+ BRAF- Good PS

• 1. Clinical Trial
• 2. Ipilimumab/nivolumab
• 3. Pembrolizumab or nivolumab
• 4. T-VEC
• 1. Clinical Trial
• 2. Pembrolizumab or

nivolumab

• 1. Clinical trial
• 2. BRAF/MEK inhibitor(s)
• 3. Pembrolizumab or

nivolumab

Surgical candidate Poor PS Yes ¡ No ¡

• 1. Ipilimumab/nivolumab
• 2. BRAF/MEK inhibitor combination
• 3. Ipilimumab
• 4. Interleukin-2
• 5. T-VEC
• 6. Clinical Trial
• 7. Chemotherapy

EORTC 18071/CA184-029: Study Design

Ipilimumab vs Placebo after complete resection of stage III melanoma

LBA 9008, presented By Alexander Eggermont at 2014 ASCO Annual Meeting

Primary Endpoint: Recurrence-free Survival (IRC)

Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

Slide 15

Presented By Alexander Eggermont at 2014 ASCO Annual Meeting

Adjuvant nivolumab vs ipilimumab in resected stage III

• r IV melanoma

Weber J NEJM online Sept 10 2017

Prospective randomized trial in completely resected stage IIIB, IIIC, or IV melanoma Nivolumab 3 mg/kg q 2 wk (n = 453) vs Ipilimumab 10 mg/kg q 3 wk x 4, then q 12 wks (n= 453)

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BID, twice daily; DMFS, distant metastasis–free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free

• survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; b Patients were followed for disease recurrence until the first recurrence and thereafter for survival;

c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are lost to follow-up; d New primary melanoma considered as an event.

COMBI-AD: STUDY DESIGN

Key eligibility criteria

• Completely resected, high-risk stage IIIA

(lymph node metastasis > 1 mm), IIIB,

• r IIIC cutaneous melanoma
• BRAF V600E/K mutation
• Surgically free of disease ≤ 12 weeks

before randomization

• ECOG performance status 0 or 1
• No prior radiotherapy or systemic

therapy

R A N D O M I Z A T I O N Stratification

• BRAF mutation status (V600E, V600K)
• Disease stage (IIIA, IIIB, IIIC)

1:1

Dabrafenib 150 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) Treatment: 12 monthsa

Follow-upb until end of studyc

• Primary endpoint: RFSd
• Secondary endpoints: OS, DMFS, FFR, safety

N = 870

60

RELAPSE-FREE SURVIVAL (PRIMARY ENDPOINT)

438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3

Months From Randomization

Dabrafenib plus trametinib Placebo

• No. at Risk

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Proportion Alive and Relapse Free

1 y, 88% 2 y, 67% 3 y, 58% 1 y, 56% 2 y, 44% 3 y, 39%

NR, not reached.

Group Events, n (%) Median (95% CI), mo HR (95% CI) Dabrafenib plus trametinib 166 (38) NR (44.5-NR) 0.47 (0.39-0.58 ); P < .001 Placebo 248 (57) 16.6 (12.7-22.1)

P = .0000000000000153

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OVERALL SURVIVAL (FIRST INTERIM ANALYSIS)

438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Proportion Alive

1 y, 97% 2 y, 91% 3 y, 86% 1 y, 94% 2 y, 83% 3 y, 77%

a Prespecified significance boundary (P = .000019).

Months From Randomization

Group Events, n (%) Median (95% CI), mo HR (95% CI) Dabrafenib plus trametinib 60 (14) NR (NR-NR) 0.57 (0.42-0.79 ); P = .0006a Placebo 93 (22) NR (NR-NR)

Dabrafenib plus trametinib Placebo

• No. at Risk

Adjuvant radiation for resected, high-risk melanoma

Henderson MA Lancet Oncol 16:1049, 2015

250 pts with resected stage III melanoma at high risk of nodal relapse Randomly assigned to: Adjuvant radiotherapy (48 Gy in 20 fractions) (N = 109 eligible) Observation (N = 108)

Henderson MA Lancet Oncol 16:1049, 2015