Immunotherapy for the Treatment of Melanoma Marlana Orloff, MD Thomas Jefferson University Hospital
Disclosures Immunocore and Castle Biosciences, Consulting Fees I will be discussing non-fda approved indications during my presentation.
Types of Immunotherapies for Melanoma Cytokines Interferon-α 2b Interleukin-2 Oncolytic Virus Modified Herpes Virus (Talimogene Laharparepvec; TVEC) Checkpoint antibodies Anti-CTLA4 (ipilimumab) Anti-PD1 (pembrolizumab, nivolumab) (Avelumab for Merkel cell carcinoma March 2017)
Adjuvant Treatment of High-Risk Melanoma Mocellin et al. JNCI. 2010
http://www.sinobiological.com/interferon-side-effects-a-6085.html Toxicity of Adjuvant Interferon-α
High Dose Interleukin-2 Therapy (HD IL-2) : Durable Responses HD IL-2 produces durable responses in 6%-10% of patients with advanced melanoma Few relapses in patients responding for over 2.5 years (cured?) FDA approval for melanoma in 1998 High toxicity Atkins et al. J Clin Oncol. 1999 Atkins et al. J Clin Oncol. 1999
Phase III Trial of T-VEC vs GM-CSF PFS per Investigator Melanoma months Andtbacks et al. ASCO 2013; LBA9008
Ipilimumab & Immune Check-Point Blockade 22% Luke et al, Oncologist 2013 Schadendorf et al, J Clin Oncol 2015
Case #1: Adjuvant 54 year old female with partially regressed primary melanoma on her cheek and parotid swelling Underwent excision of suspicious regressed lesion, parotidectomy and left neck dissection Primary melanoma 0.86mm with evidence of brisk tumor lymphocyte infiltration and regression Parotid involvement and 8/58 nodes positive with evidence of matting and extra-nodal extension
Case #1: Adjuvant Underwent adjuvant radiation Followed by adjuvant Ipilimumab 3 mg/kg with option for every 3 month maintenance Complete maintenance x2 with no evidence of local or systemic recurrence
Eggermont et al. NEJM 2016 Adjuvant Ipilimumab in High-Risk Melanoma
HD-IFN or IPI-3 or IPI-10 Adjuvant study was versus observation Tarhini et al Phase II and Phase III studies presented at ASCO Phase II study of IPI3 or IPI10 alone or in combo with HDI There were no significant differences in PFS with HDI vs. no HDI or ipi10 vs. ipi3 Phase III study of IPI-3 or IPI-10 versus HDI Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. J Clin Oncol 35, 2017 (suppl; abstr 9542) J Clin Oncol 35, 2017 (suppl; abstr 9500)
Anti-PD1 (pembrolizumab) after ipilimumab Anti-PD1 in Melanoma Front-line anti-pd1 (nivolumab) vs. DTIC in Melanoma (BRAF WT) Front-line anti-pd1 (pembrolizumab) vs. ipilimumab Robert et al, NEJM 2015 Robert et al, Lancet 2014 Robert et al, NEJM 2015
Three Year Overall Survival N Median OS (95% CI), mo 24-mo OS Rate, % 36-mo OS Rate, % Pembro 2 Q3W 162 23.5 (18.3-35.0) 49 38 Pembro 10 Q3W 313 22.9 (18.5-31.1) 49 39 Pembro 10 Q2W 180 25.9 (18.9-41.8) 52 43 Ipi treated 342 20.0 (17.8-27.1) 46 41 Ipi naive 313 28.8 (23.1-32.2) 54 41 Treatment naive* 149 32.0 (27.1-NR) 60 45 Robert et al. J Clin Oncol 34, 2016 (suppl; abstr 9503)
Ipilumamab: Nivolumab: CTLA-4 PD-1 Ipi+Nivo vs. Ipi or Nivo vs. Ipi in Melanoma Presented by Jedd Wolchok at ASCO 2015 - Wolchok et al. J Clin Oncol 33, 2015 (suppl; abstr LBA1)
Ipilumamab: Nivolumab: CTLA-4 PD-1 Ipi+Nivo vs. Ipi or Nivo vs. Ipi in Melanoma: Checkmate 067 Presented by Jedd Wolchok at ASCO 2015 - Wolchok et al. J Clin Oncol 33, 2015 (suppl; abstr LBA1)
Orloff Et al Rev Recent Clin Trials. 2016;11(2):81-6 Larkin Et al N Engl J Med. 2015 Jul 2;373(1):23-34
Ipilumamab: Nivolumab: CTLA-4 PD-1 Ipi+Nivo vs. Ipi or Nivo vs. Ipi in Melanoma Presented by Jedd Wolchok at ASCO 2015 - Wolchok et al. J Clin Oncol 33, 2015 (suppl; abstr LBA1)
Case #2: Metastatic 56 year old female who was diagnosed with a 2.6 mm melanoma of the left chest in 2012 Negative SLN biopsy No routine oncologic or dermatologic follow up November 2015 developed RUQ pain Found to have rib lesion, enlarged mediastinal nodes, and pulmonary nodules Biopsy proven metastatic melanoma BRAF V600E mutation
11/15/2015
Case #2: On 12/29/15 the patient initiated combination immune checkpoint inhibitor therapy Ipilimumab (3 mg/kg) Nivolumab (1 mg/kg) She presented for evaluation of the rash on 1/11/16 and started on prednisone taper. Presented 1/19/16 and since her rash had resolved and she was feeling well Proceeded with treatment with nivolumab alone One day later called with recurrence of shortness of breath
1/20/2016
Case #2: Initiated on high dose IV steroids Rapid resolution of pulmonary symptoms with radiologic and clinical improvement Has remained off active treatment since
2/16/2016
11/15/2015 3/9/2017
Ipi-Nivo vs Nivo Overall Response Rate in Patient Subgroups
Wolchok et al. Clin Can Res 2009 Immune Related Response Criteria
Wolchok et al. Clin Can Res 2009 Immune Related Response Criteria
Best Therapies Clinical Trials Adoptive T Cell Therapy Tumor-infiltrating lymphocytes (TILs) Neoantigen vaccines Oncolytic virotherapy New/improved immune checkpoint blockers w/immunomodulators of resistance (indoleamine dioxygenase inhibitors) agonistic costimulatory antibodies (CD137, OX40) hypofractionated or stereotactic radiotherapy Molecularly-focused treatment paradigms all immunomodulatory Metabolic reprogramming Next generation sequencing molecular drivers and/or modifiers
On-Going Phase III Trials in Melanoma BRAFi + MEKi + anti PD-(L)1 MEKi + anti PD-(L)1 Indolamine Dioxygenase inhibitors (IDOi) + anti PD-(L)1 Talimogene laharparepvec (TVEC) + anti PD(L)1
Target-Immuno Triplets: BRAF + MEK + PD1/L1 Dabrafenib+Trametinib+ Durvalumab Dabrafenib+Trametinib+ Pembrolizumab Vemurafenib+Cobimetinib+ Atezolizumab 100 75 Change From Baseline, % 50 25 0-25 -50-75 Change From Baseline in Sum of Longest Diameter of Target Lesion, % -100 0 10 20 30 40 50 60 70 100 Time, weeks 80 60 40 20 0-20 -40-60 -80-100
Target-Immuno Triplets: BRAF + MEK + PD1/L1 Dabrafenib+Trametinib+ Durvalumab Dabrafenib+Trametinib+ Pembrolizumab Vemurafenib+Cobimetinib+ Atezolizumab 100 75 50 25 Multiple Triplet Combinations Launching Into Phase III: 0-50 -75 - Dabrafenib + Trametinib -100 + Pembrolizumab 0 10 20 30 40 50 60 70 Time, weeks 100 - Dabrafenib + Trametinib 80 + PDR-001 60 40 - Vemurafenib + Cobimetinib 20 + Atezolizumab Change From Baseline in Sum of Longest Diameter of Target Lesion, % Change From Baseline, % -25 0-20 -40-60 -80-100
MEK inhibitor + PDL-1 for BRAFwt Melanoma Phase I Cobimetinib + Atezolizumab Phase III Study of Cobimetinib + Atezolizumab versus Pembrolizumab in Patients with Untreated BRAFV600 Wild-Type Melanoma PROTOCOL NUMBER: CO39722 Atezolizumab: PD-L1 Pembrolizumab : PD-1
IDO inhibitor epacadostat + pembrolizumab Phase 1/2 Study of Epacadostat (INCB024360) + Pembrolizumab in Patients With Melanoma A Phase 3 Study of Pembrolizumab + Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma (Keynote-252 / ECHO-301) ClinicalTrials.gov Identifier: NCT02752074 RECIST response = 58%, no increase in toxicity from pembrolizumab alone Beatty et al. ASCO (2012) Abstract 2500 Gangadhar et al. ESMO 2016 Zakharia et al AACR 2017 (indoximod)
T-Vec + Pembrolizumab in Stage IIIB-IV Melanoma Long et al. SMR 2015 RECIST response = 46%, no increase in toxicity from pembrolizumab alone
Conclusions Immunotherapy is standard of care in melanoma Likely first and second line in most patients Understanding mechanisms of action important Manage side effects, understand long-term benefit Immunotherapy combinations are likely the future for melanoma and likely all cancers!