gary c. doolittle, md capitol federal masonic professor ......treatment of metastatic melanoma...

NEW THERAPEUTIC OPTIONS FOR THE TREATMENT OF MALIGNANT

MELANOMA

Gary C. Doolittle, MD Capitol Federal Masonic Professor Clinical Oncologist University of Kansas Cancer Center

… there ARE therapeutic options for the treatment of malignant melanoma!

Overview

Therapeutic Options:

• Adjuvant Therapy

– Interferon

– Chemotherapy

• Metastatic melanoma

– Targeted treatment

– Immunotherapies

THERAPY FOR MELANOMA IN THE ADJUVANT SETTING

TNM 5-year

Stage classification Definition survival rate

IIB T3b N0M0 T 2.01-4.0 mm, ulceration 63% T4a N0M0 T >4.0 mm, no ulceration 67%

IIC T4b N0M0 T >4.0 mm, ulceration 45%

IIIA AnyTN1a M0 1 micro node, no ulceration 69%

AnyTN2a M0 2-3 micro nodes, no ulceration 63%

IIIB AnyTN1a M0 1 micro node, ulceration 53%

AnyTN2a M0 2-3 micro nodes, ulceration 50%

AnyTN1b M0 1 macro node, no ulceration 59%

AnyTN2b M0 2-3 macro nodes; no ulceration 46%

IIIC AnyTN1b M0 1 macro node, ulceration 29%

AnyTN2b M0 2-3 macro nodes, ulceration 24%

AnyTN3 M0 4 nodes, matted nodes or nodes + in-transit 27% metastasis

J Clin Oncol. 2001;19:3635-3648.

Rationale for Adjuvant Treatment

Adjuvant Treatment of High Risk Primary Disease

• High risk:

– Greater than 4 mm primary

– 2-4 mm with the presence of ulceration (Stage IIB)

– Lymph node positive (Stage III) disease

• Treatment options:

– High Dose Interferon

– Pegylated Interferon

Mocellin et al, , JNCI, 2010; 102: 493-501

What Do We Know About IFN in the Adjuvant Setting?

Adjuvant Therapy for High Risk Disease

• High dose interferon improves relapse free and overall survival

– Traditional dose schedule:

• Four weeks of high dose intravenously

• Forty eight weeks, thrice weekly subcutaneously

– High dose IFN versus Intermittent IFN:

• ‘standard’ versus four weeks of HDI three times in one year

• Most studies for cutaneous melanoma

– One adjuvant study for mucosal primaries

• Side effects with interferon are substantial

Adjuvant Treatment—Pegylated Interferon

• Pegylated Interferon randomized trial

– Induction 6ug/kg/week; maintenance 3 ug/kg/week

– Dose reduction to 2, 3, 1 to maintain performance status

• for node + patients

• Treatment Schema:

- Induction: 8 weeks: 6ug/kg per week

- Maintenance: 3ug/kg per week

- Five year treatment course

- Doses reduced to maintain ECOG PS of 0 or 1

Adjuvant Treatment—Pegylated Interferon

• Results:

- Improved relapse-free survival

- No improvement in overall survival

• Who benefits?

- Ulcerated primary lesions

- Lower disease burden, N1 patients

Eggermont, Suciu, Testori et al: Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma. JCO 30: 3010-3818, 2012

Adjuvant Therapy for High Risk Disease

High dose interferon versus biochemotherapy—SWOG S0008 – Phase III trial, Cisplatin, Velban, DTIC, IL-2 and interferon

– RFS: 47% versus 39%, BCT vs. IFN, statistically significant

– Overall survival: 56%, no difference

Toxicity: – BCT: more hematologic, GI and metabolic toxicity

– IFN: more hepatic, neuro/ psych toxicity

BCT - Does not replace IFN as standard of care

BCT - for selected patients

- RFS longer

Flaherty, et al, ASCO Annual Meeting, 2012

Adjuvant Avastin for Resected High-Risk Melanoma: AVAST-M

• Prospective, randomized trial of 1320 patients

• Stages IIB,, IIC or III subjects with cutaneous melanoma

• SLNB recommended but not mandatory

• Treatment:

• Bevacizumab (7.5mg/ kg, IV every three weeks for one year) versus observation

• Primary endpoint: overall survival

• Secondary endpoints: DFS, safety, toxicity, QOL

Adjuvant Avastin for Resected High-Risk Melanoma: AVAST-M

• Baseline characteristics balanced for age, gender, performance status, stage, Breslow thickness, presence of ulceration, SLNB performed and N classification

• 54% completed planned treatment

• Discontinued due to disease recurrence, toxicity, patient choice, death, other

• Findings:

No improvement in OS, DFS did improve, well tolerated

Corrie, et al, ASCO, 2013, UK NCRI Melanoma Clinical Studies Group

Disease-free Interval (DFI)

Presented By Philippa Corrie, PhD, MRCP, FRCP at 2013 ASCO Annual Meeting

Overall Survival

Presented By Philippa Corrie, PhD, MRCP, FRCP at 2013 ASCO Annual Meeting

Adjuvant Therapy for Resected High-Risk Melanoma

• High-dose IFN-α2b and peg-IFN are both FDA approved as adjuvant therapy for resected stage IIB/III melanoma

• High-dose IFN may be best for stages IIIb/IIIc resected disease; peg-IFN may be more useful for ulcerated stage II disease and stage IIIa microscopic disease

• For both treatments, prolonged RFS but only modest evidence of increased OS has been observed

• Avastin?

• Biochemotherapy?

RFS = recurrence-free survival Mocellin et al, 2010; NCCN, 2011; Kaehler et al, 2010; Okuyama et al, 2010.

Future Study in the Adjuvant Population?

• Standard of care is still interferon

• Questions to address:

– Immune versus targeted versus chemotherapy

– What should the control arm be?

– What is the end point? RFS? OS

• Clinical trial participation is essential!

– ECOG 1609 Study

• Ipilimumab versus standard interferon

– Roche/ Genentech

• Vemurafenib versus placebo

THERAPY FOR MELANOMA IN THE METASTATIC SETTING

Treatment of Metastatic Melanoma Chemotherapy

– DTIC

– Biochemotherapy

– Temozolamide

– Temozolamide/ Thalidomide

– Carboplatin/ Taxol

Treatment of Metastatic Melanoma

Targeted agents – Vemurafenib

– Dabrafenib

– Trametinib

– Vemurafenib and trametinib

Immunotherapy – High dose IL-2

– Ipilimumab

– Ipilimumab + GM CSF

– PD 1 inhibitors

– PD-1 inhibitor (Nivolumab) and Ipilimumab

– Anti-PD-1 antibodies: Lambrolizumab

Targeted Agents

Treatment of Metastatic Melanoma The RAS/RAF/MEK Pathway

Distribution of BRAF/NRAS/cKIT Mutations by Site of Primary

A New Way to Classify Melanomas

CSD = chronic sun-damaged skin Curtin et al, 2006

BRIM 3: The Vemurafenib Story

• Phase III Trial of metastatic patients with no prior treatment

• Vemurafenib (960 mg BID) versus dacarbazine (1000mg/ M2 every three weeks)

• 675 patients randomized

• Primary endpoints: – Progression free survival

– Overall survival

• Secondary endpoints: – Response rate

– Response duration

– Safety

BRIM 3: Progression-free Survival

Chapman PB et al. N Engl J Med 2011;364:2507-2516

BRIM 3: Overall Survival

Chapman PB et al. N Engl J Med 2011;364:2507-2516

BRIM3: Selected Adverse Events

Vemurafenib, n= 336 Dacarbazine, n= 282

Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4

Arthralgia 49 3 - 3 <1 -

Rash 36 8 - 1 - -

Fatigue 33 2 - 31 2 -

Photosensitivity 30 3 - 4 - -

LFTs 18 7 <1 5 1 -

Cutaneous SCC 12 12 - <1 <1 -

Keratoacanthoma 8 6 - - - -

Skin papilloma 18 <1 - - - -

Nausea 30 1 - 41 2 -

Neutropenia <1 - <1 11 5 3

Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine Chapman PB et al. N Engl J Med 2011;364:2507-2516

Vemurafenib and the Skin

Vemurafenib and the Skin

BREAK-3: The Dabrafenib Story

• Dabrafenib inhibits BRAF V600e kinase

• Phase III, randomized study in which patients received dabrafenib (150 mg BIS) or Dacarbazine (1000mg/ M2 IV every three weeks)

• Stratified, unresectable Stage III, IVa, IVb, and IVc

• Primary endpoint: progression free survival

Hauschild, et al. Lancet 2012; 380:358-65

BREAK-3: The Dabrafenib Story

Hauschild, et al. Lancet 2012; 380:358-65

BREAK-3: the Dabrafenib Story Progression-Free Survival

Hauschild, et al. Lancet 2012; 380:358-65

BREAK-3: The Dabrafenib Story

Adverse events with dabrafenib:

• Arthralgias

• Asthenia

• Fatigue

• Headache

• Pyrexia (8%)

• Skin: – Hyperkeratosis

– Palmar-plantar hyperkeratosis

– Squamous cell carcinoma/ keratoacanthoma

• Nausea/ vomiting

METRIC: The Trametinib Story

• MEK Inhibitor

• Phase III, randomized trial treating with trametinib (2mg orally daily) or Dacarbazine (1000mg per M2) or taxol (175 mg/M2 every three weeks)

• Chemotherapy patients crossed over to trametinib upon progression

• Primary endpoint: progression free survival

Flaherty KT et al. N Engl J Med 2012;367:107-114

METRIC: The Trametinib Story

Flaherty KT et al. N Engl J Med 2012;367:107-114

METRIC: The Trametinib Story

Flaherty KT et al. N Engl J Med 2012;367:107-114

METRIC: The Trametinib Story

Flaherty KT et al. N Engl J Med 2012;367:107-114

METRIC: The Trametinib Story

Flaherty KT et al. N Engl J Med 2012;367:107-114

METRIC: The Trametinib Story

Flaherty KT et al. N Engl J Med 2012;367:107-114

What about combination treatment? Dabrafenib and Trametinib

• Theory: resistance to BRAF inhibitors is associated with reactivation of the MAPK pathway

• To address: combine BRAF inhibitor to MAPK MEK inhibitor

• Phase I/ II trial – open-label randomized study of dabrafenib (75mg or 150 mg

twice daily) and trametinib (1 mg or 1.5 mg or 2.0 mg once daily) in eighty five patients

– Randomly assigned to receive combination dabrafenib (150 mg) with trametinib (1 or 2 mg)

Flaherty KT et al. N Engl J Med 2012;367:1694-1703

What about combination treatment?

Flaherty KT et al. N Engl J Med 2012;367:1694-1703

Dabrafenib and Trametinib

Flaherty KT et al. N Engl J Med 2012;367:1694-1703

Dabrafenib and Trametinib

Flaherty KT et al. N Engl J Med 2012;367:1694-1703

Dabrafenib and Trametinib

Flaherty KT et al. N Engl J Med 2012;367:1694-1703

Immunotherapies: Anti-CTLA 4 agents

Anti-PD-1 agents

Anti-PD-L1 agents

Anti-CTLA4 Antibodies

• CTLA-4

– Molecule expressed on the surface of the activated T-lymphocytes

– CTLA-4 can restrict the antitumor immune response of T cells

• CTLA-4 antibodies result in increased T cell activation

• Treatment for at least 12 weeks

Ipilimumab Is a Member of a Novel Class of Immunotherapeutic Antibodies

.

Ipilimumab Plus DTIC vs. DTIC Alone (Study 024): Design

Dacarbazine 850 mg/m2 q3wks x8

SCREENING INDUCTION MAINTENANCE

Previously untreated Metastatic Melanoma (N = 502)

Ipilimumab 10 mg/kg q3wks x4

Placebo q3wks x4

Ipilimumab 10 mg/kg q12wks

Placebo q12wks

Dacarbazine 850 mg/m2 q3wks x8

Wk 12 Wk 24

Baseline tumor assessment

First scheduled tumor assessment

R

Wk 1

2In absence of progression. Wolchok et al, 2011.

= blinded

randomization (1:1) R

Side Effect Profile For Ipilimumab

• Immune-mediated: – Dermatologic

• Rash

– Gastrointestinal

• Colitis/diarrhea

– Endocrine

• Pituitary dysfunction

Management of Side Effects:

• Patient education for early recognition

• Maintain close contact with patient

• Aggressive work-up and management for moderate/severe events

• Non-specific complaints

– May reflect endocrine (e.g., pituitary) toxicity

• Established therapies (e.g., corticosteroids) are effective, may need other immunosuppressive agents, and reporting

Summary of Ipilimumab Data

• First agent to show survival improvement in metastatic melanoma

• Survival rates in ipilimumab studies:

– 1 yr: 44%, 46%

– 2 yrs: 22%, 24%

• Consistent superiority of ipilimumab for all secondary efficacy end points

– PFS, BORR, DCR Hodi et al, 2010.

Can Ipilimumab be Improved by Adding GM-CSF?

• Immunologic rationale

-GM-CSF enhance dendritic cell activation, potentiates antitumor T and B cell responses

- GM-CSF is widely available and may have immunomodulatory properties in melanoma

- Synergy between CTLA4 blockade and GVAX was shown in mice with established melanoma

. Hodi et al, 2013

Can Ipilimumab be Improved by Adding GM-CSF?

ECOG 1608 Study: Eligibility: measureable disease, ≤1 prior therapy, no CNS mets, ECOG PS 0-1, > 4 wks prior therapy, adequate end organ function, no autoimmune disease, no prior CTLA-4 blockade/CD137 agonist.

Endpoint: overall survival

Randomized to receive: Arm A Ipi 10 mg/kg q3 wks IV x 4 then q12 wks plus GM 250 μg SC days 1-14 of 21 day cycles Arm B Ipi 10 mg/kg as in Arm A alone.

Hodi et al, ASCO 2013

Can Ipilimumab be Improved by Adding GM-CSF?

Results:

• 245 pts were enrolled. Arms were balanced for demographics. Median follow up 13.3 mos

• IPI + GM-CSF: Response rate 11.3%

Median OS 17.5 months

• IPI Alone: Response rate 14.7% Median OS 12.6 months

• Toxicity? Side effect profile?

Fewer grade 3-5 side effects Hodi et al, 2013

PD-1/ PD-L1 as Immune Targets

Programmed death-1, or PD-1, is an inhibitory receptor expressed by activated T-cells. It is a member of the CD28 family of receptors, which are involved in T cell regulation. PD-1 is activated by its ligand, PD-L1, which is expressed primarily on lymphoid and restricted non-lymphoid tissues. The physiologic role of the PD-1/PD-L1 interaction is to prevent uncontrolled immune activation during chronic infection or inflammation. However, when PD-1 is bound by PD-L1, the ability of the activated T-cell to produce an effective immune response against cancer cells is downregulated. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175.

PD-1/ PD-L1 as Immune Targets

Lambrolizumab (Anti-PD-L1) in the Treatment of Melanoma

Inclusion Criteria: Advanced, unresectable melanoma No restriction on prior therapies ECOG 0 or 1 Adequate Organ Function

Exclusion Criteria

Systemic corticosteroid therapy Active autoimmune disease Active and untreated CNS metastases

CNS metastases eligible if > 2 months Uveal melanoma

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1

Hamid O et al. N Engl J Med 2013;369:134-144

Lambrolizumab (Anti-PD-L1) in the Treatment of Melanoma

Conclusions:

• Treatment with lambrolizumab resulted in a high rate of tumor regression with a favorable toxicity profile

• Cohort treated at 10 mg/kg every two weeks showed the highest response rate (52%)

• Highest rate of drug-related side effects

• Randomized trial comparing 10mg/kg every 2 versus every 3 weeks

• Caution with cross study comparisons! ….ipilimumab studies

• Fewer immune-related adverse events Hamid O et al. N Engl J Med 2013;369:134-144

Nivolumab plus Ipilimumab in Advanced Melanoma

Phase I Study: data for 86 patients; PD-1; PD-L1 immunohistochemical testing prior to study entry

• Escalating doses of IV nivolumab and ipilimumab

• Ipilimumab and nivolumab every three weeks four total of four doses

• Combination therapy every 12 weeks for up to eight doses

• Sequential therapy cohort

Hamid O et al. N Engl J Med 2013;369:134-144

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

ANTI-PD-1 & IPILIMUMAB

Wolchok JD et al. N Engl J Med 2013;369:122-133

New Treatment Algorithm for Stage IV Melanoma

• Treatment naïve

– High dose IL-2 eligible

– High priority protocol if eligible

– Vemurafenib or imatinib if tumor mutated

– Ipilimumab alone or with other drugs if not mutated

• Previously treated

– High priority protocol if eligible

– High dose IL-2, vemurafenib or imatinib if appropriate

– Standard therapy, or phase I or II protocol

• Low tumor burden: immunoRx; High Burden: BRAF inhibitor

Metastatic Melanoma: Clinical Trial Prospects - 2013

• Clinical trial preferred for all patients to answer key therapeutic questions

– Ipilimumab dose and schedule, induction and maintenance

– Vemurafenib + ipilimumab

– Addition of MEK inhibitor to mutant BRAF inhibitor

• Addition of agents blocking pathways responsible for resistance

– Targeted agent trials for NRAS mutant and WT population (15% and 35%)

– Combination immunotherapies

– Combination with chemotherapy and anti angiogenic agents

MELANOMA MONDAY

QUESTIONS?

Gary C. Doolittle gdoolitt@kumc.edu