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1 Winship Cancer Institute of Emory University

Combination therapy in melanoma: ready for primetime?

Ragini Kudchadkar, MD

Disclosures

• Fees from non‐CME services such as speaker’s

bureaus:

– Bristol‐Myers Squibb, Genentech

2 Winship Cancer Institute of Emory University

Medical Oncology Rule # 1: If one drug works, then two will work better.

Winship Cancer Institute of Emory University

CRAF BRAF MEK 1/2 PI3K PDK1 PIP2 FOXO RAS TKR Growth Factors: VEGF, PDGF, FBGF, FLT-3 ARAF ERK 1/2 PIP3 PTEN AKT MTOR

Pro-Growth Pro-apoptosis

MITF CDK4 Cyclin D CDK2 P16 CKIT

3 BRAFV600E melanoma patient PET scan at baseline and day 15 after vemurafenib treatment

MISSION ACCOMPLISHED!

Day 15 Baseline

Flaherty K et al. N Engl J Med 2010;363:809

Vemurafenib Single Agent Activity

• BRIM‐3 Vem vs DTIC in treatment naïve ‐ McArthur et al

Lancet Oncology 2014

– 675 patients randomized, though cross over was allowed once benefit was established – Median OS 13.6 months vs 9.7 – Median PFS 6.9 months vs 1.6

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Dabrafenib Single Agent Activity

• BREAK‐3 Dabrafenib vs DTIC in treatment naïve ‐ Hauschild

et al Lancet 2012

• 250 patients randomized, 187 to dabrafenib vs 63 to

dacarbazine

– Median PFS 5.1 vs 2.7 months

Rationale for Combination Therapy

pERK

BRAF MEK

Proliferation, Survival, Invasion, Metastasis Dabrafenib Trametinib

RAS

RR 63%1 RR 40%1

1 Data presented at ASCO 2010

Goals of Combination

• 1. Synergy in combination
• 2. Prevent/overcome potential

monotherapy resistance

• 3. Potentially decrease incidence of

BRAFi-induced hyper-proliferative skin lesions

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Dabrafenib vs Dabrafenib + Trametinib

• D + T (2mg)

– PFS 9.4 mo – RR (CR +PR) 76% – SD 24%

• D + T (1mg)

– PFS 9.2 – RR 50% – SD 44%

• D

– 5.8 mo – RR 54% – SD 41%

• Combination therapy had more pyrexia (71% vs

26%) but less cutaneous squamous cell carcinomas (7% vs 19%) Flaherty KT et al. N Engl J Med 2012;367:1694-1703.

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Is combination better?

• Statistically, yes.
• PFS 9.3 vs 8.8 months, HR 0.75
• Clinically, unknown.

– Most experts say yes – We were convinced with phase II data but did we drink the kool‐aid? – Lots of statically jargon to say yes. Early censoring in the dabrafenib arm lead to “better” single agent activity than expected

• By side effects, toss up.

– Much less skin toxicity – Higher rate of fevers

• Fiscally, no.

– Single agent costs 8‐10K a month, Combination approximately 18K per month

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My opinion…

• Combination is better

– PFS is better statistically, though not as dramatic as expected – Fevers easier to control and tolerate than the skin toxicity – In the end we are all influenced by our practice and I have many more longer term survivors on combination therapy than on single agent – Awaiting results of other combination studies from other BRAF/MEK inhibitors to finalize my

• pinion

Winship Cancer Institute of Emory University

Combination Immunotherapy

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Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14%

Ipi + gp100 (A) Ipi alone (B) gp100 alone (C)

1 2 3 4

Years

Hodi et al. N Engl J Med 2010;363:711

Single Agent IPI (3mg/kg)

Topalian SL et al. N Engl J Med 2012;366:2443-2454

• Melanoma Responses

– 26 of 94 patients – At 3mg/kg 7/17 41% RR

• PDL‐1 staining

– All tumor types – Positive 9/25 – Negative 0/17 – Results have not held true in other studies

• PDL1 positive respond at a higher rate, but

PDL1 negative can respond

Phase I Study of Nivolumab

In nivolumab-treated pts: 1-yr OS 62% 2-year OS 43% Topalian et al JCO 2014

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http://dx.doi.org/10.1016/S0140-6736(14)60958-2 Robert C et al Lancet 2014

Pembrolizumab in IPI refractory

Context: Nivolumab compared to Pembrolizumab?

Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

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• Tolerable dose: IPI 3mg/kg + Nivo 1mg/kg
• 21/52 (40%) ORR
• “Rapid and Deep Responses”
• Toxicity

– 93% ALL grades, treatment related – Grade 3/4 Toxicity 53%

• Elevated lipase, AST, ALT
• 21% Dose‐limiting
• PDL‐1 Staining

– 6/13 PDL‐1 positive – 9/22 PDL‐1 negative

Ipi + Nivolumab: Do we need Phase III data?

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

Combination Immunotherapy

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Is combination better?

• Unknown – await phase III data

– We’ve been fooled before, but early data is very promising

• Toxicity may be the limiting factor

– Will the combination need to be used in specific centers like HD‐IL2?

• Will sequencing of therapies be just as good

with less toxicity?

– Sequencing trial data is pending

Conclusion

• Combination therapy is the way of the future.
• The next frontier will better define how to

combine both immunotherapy with targeted tyrosine kinase inhibitors.

• A word of caution, more is not always better.