Metastatic Melanoma - New therapies and their toxicities ... · New therapies and their toxicities...

Metastatic MelanomaNew therapies and their

toxicitiesMelissa Eastgate

Deputy Director Medical OncologyChair, Melanoma MDT RBWH

RBWH21 July 2018

Question 1:

• How many people die in Australia each year from melanoma?a) 300b) 1600c) 10000

Question 2:

• What is the 2 year survival for someone with metastatic melanoma treated with immunotherapy?a) 10%b) 30%c) 55%

Melanoma Incidence in Australia

• 2015– 1675 deaths – 12960 new cases– 3.6% of cancer deaths

AJCC staging – 8th edition

• T1 measured to 1 decimal place not 2• Tumour mitotic rate removed

0 1 2 3 4 5 6 7 8

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Yrs

Prop

ortio

n Su

rviv

ing

9 10 11 1312 14 15

Stage I (n = 9175)

Stage II (n = 5739)

Stage III (n =1 528)

Stage IV (n = 1158)

Survival in Melanoma by Stage

Balch CM, et al. J Clin Oncol. 2001;19:3635-3648.

Melanoma skin cancer incidence and mortality, 1968 to 2012

Where can we make a difference?

• Prevention/early detection• Better neo/adjuvant therapy• Improved treatment in the advanced setting.

– Downstage to enable curative treatment– Picking the right treatment for the right patient– Prolong overall survival

• Reduced toxicity of treatment

Metastatic melanoma available treatment: 1970–2015

<1990 2000 2010 201420122011 2013 2015

Proleukin(high-dose IL-2)

Jan 1998

DTIC-Dome (dacarbazine)

1970s

DTIC-Dome (dacarbazine)

May 1975

Yervoy(ipilimumab)

Jul 2011

Zelboraf(vemurafenib)

Feb 2012

Yervoy(ipilimumab)

Mar 2011Keytruda

(pembrolizumab)

Sep 2014

Zelboraf(vemurafenib)

Aug 2011

Tafinlar/Mekinistmonotherapies

(dabrafenib/trametinib)

May 2013

Tafinlar + Mekinist(dabrafenib + trametinib)

dual therapyJan 2014

Opdivo (nivolumab)

Dec 2014

Tafinlar + Mekinistdual therapy(dabrafenib + trametinib)

Aug 2015Tafinlar

(dabrafenib)

Sept 2013

Keytruda(pembrolizumab)

July 2015

Opdivo (nivolumab)

June 2015

Sentinel Lymph Node biopsy

• Very important prognostic factor• Should be discussed with patients if

melanoma is >1mm thick• Can’t be done after WLE

Surgery for melanoma

• No benefit for completion LN dissection in patients with a positive sentinel node now confirmed in 2 studies

IMMUNOTHERAPY

Drug classes

• Anti CTLA4 antibody – Ipilimumab

• PD1/PDL1 inhibitors– Pembrolizumab– Nivolumab

Pembrolizumab Versus Ipilimumab For Advanced Melanoma: <br />Final Overall Survival Analysis of KEYNOTE-006

Presented By Jacob Schachter at 2016 ASCO Annual Meeting

Overall Survival

Presented By Jacob Schachter at 2016 ASCO Annual Meeting

Updated Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-naïve Patients With Advanced Melanoma (Checkmate 067)

Presented By Jedd Wolchok at 2016 ASCO Annual Meeting

Progression-Free Survival (Intent-to-Treat Population)

Presented By Jedd Wolchok at 2016 ASCO Annual Meeting

Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV

Melanoma: Updated Results from a Phase 3 Trial (CheckMate 238)

Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10

Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15

Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19*

1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas, USA; 7Hospices Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and University of Queensland,

Brisbane, Australia; 16University Hospital Zurich, Switzerland; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.

Abstract Number 9502

CheckMate 238: 24-Month Follow-Up

CA209-067: Study Design CheckMate 238: Study Design

Patients with:• High-risk, completely

resected stage IIIB/IIIC or stage IV (AJCC 7th

edition) melanoma• No prior systemic

therapy• ECOG 0-1

Enrollment period: March 30, 2015 to November 30, 2015

Follow-up

Maximum treatment

duration of 1 year

NIVO 3 mg/kg IV Q2W and

IPI placebo IV Q3W for 4 doses

then Q12W from week 24

IPI 10 mg/kg IV Q3W for 4 doses

then Q12W from week 24 and

NIVO placebo IV Q2W

1:1

n = 453

n = 453

Stratified by: 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c2) PD-L1 status at a 5% cutoff in tumor cells


Primary Endpoint: RFS in All PatientsR

FS (%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21 30 33

NIVOIPI

Number of patients at risk

NIVOIPI

NIVO IPIEvents/patients 171/453 221/453Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR)HR (95% CI) 0.66 (0.54, 0.81)Log-rank P value <0.0001

63%

50%

70%

60%

453 353 311 280 205 28394 331 291 264 7 0453 314 251 216 149 23363 270 230 204 5 0

66%

53%

aMedian estimate not reliable or stable due to few patients at risk.


Stage III Stage IVNIVO IPI

Events/patients 135/368 174/366

Median (95% CI) NR 25.5 (16.6, NR)

HR (95% CI) 0.68 (0.54, 0.85)

NIVO IPI


Median (95% CI) 30.8 (15.9, NR)a 15.4 (8.5, NR)

HR (95% CI) 0.68 (0.44, 1.06)

Subgroup Analysis of RFS: Disease Stage III and IV

NIVOIPI

RFS

(%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

368 291 258 230 22 0320 272 240 217NIVO 4166366 259 207 179 18 0298 223 190 169IPI 3121


72%

61%

64%

52%

NIVOIPI

RFS

(%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

82 59 51 48 6 071 56 49 45NIVO 33787 55 44 37 5 065 47 40 35IPI 228


63%

56%

58%

44%

67%

55%

61%

47%



BRAF Mutant BRAF Wild typeNIVO IPI


Median (95% CI) 30.8 (30.8, NR)a 24.6 (14.8, NR)

HR (95% CI) 0.73 (0.54, 0.99)

NIVO IPI


Median (95% CI) NR 16.6 (11.4, NR)

HR (95% CI) 0.61 (0.45, 0.82)

NIVOIPI

RFS

(%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

187 142 126 117 16 0157 135 120 110NIVO 483194 142 112 96 11 0155 118 103 91IPI 267


68%

62%

62%

52%

NIVOIPI

RFS

(%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

197 154 137 121 11 0172 144 127 115NIVO 291212 138 109 91 9 0171 121 97 85IPI 362


72%

56%

64%

46%

65%

54%

66%

49%


Subgroup Analysis of RFS: BRAF Mutation Status

If not vigilant, may result in more serious immune-related AEs

Pulmonary Pneumonitis Interstitial lung

disease Acute interstitial

pneumonitis

Neurologic Autoimmune neuropathy Demyelinating

Polyneuropathy Guillain-Barre Myasthenia gravis–like

syndrome

Hepatic Hepatitis,

autoimmune

Gastrointestinal Colitis Enterocolitis Necrotizing colitis GI perforation

Endocrine Hypothyroidism Hyperthyroidism Adrenal

insufficiency Hypophysitis

Eye Uveitis Iritis

Renal Nephritis,

autoimmune Renal failure

Skin Dermatitis exfoliative Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis Vitiligo Alopecia

Immune-Related AEs With Immunotherapy

Slide credit: clinicaloptions.com

Presenter

Presentation Notes

AE, adverse event. Skin, gastrointestinal, and endocrine toxicities following checkpoint inhibitor treatment are common whereas autoimmune hepatitis is fairly rare. Note that endocrine-related adverse events can sometimes present subtly but still may require attention.

http://www.clinicaloptions.com/oncology

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Kinetics of Appearance of irAEs With Ipilimumab

Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis

Toxi

city

Gra

de

Wks140 2 4 6 8 10 12

Combined analysis of 325 participants with 10 mg/kg IV q3w x 4


Presenter

Presentation Notes

irAEs, immune-related adverse events. As previously discussed, activation of the immune system following checkpoint inhibitor administration takes time. Similar to this delayed tumor response, adverse events also take time to show up because they are immune mediated. The kinetics of adverse event appearance were studied in a combined analysis of 325 patients receiving 10 mg/kg IV ipilimumab every 3 weeks for 4 cycles.[1] Typically, a rash was seen early on and then sometimes some diarrhea. Liver dysfunction occurred a bit later, and endocrinopathies happened very late—weeks to months after the completion of therapy. Patients should undergo complete metabolic profiling with thyroid-stimulating hormone (TSH) and liver function tests (LFTs) at baseline and before every dose of ipilimumab. In addition to thyroid issues, adrenal insufficiency can emerge. If patients present as very tired and slightly nauseous with a mild headache, a full thyroid panel with adrenocorticotropic hormone (ACTH) should be obtained to better evaluate their pituitary function. Of note, patients sometimes get a little hyperthyroid before becoming hypothyroid. Reference 1. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697.


Immune-Mediated Endocrinopathies

• Can be serious or fatal if not managed correctly

• Hypophysitis, thyroid disease, and primary adrenal insufficiency have all been reported

• Mechanism of injury not fully understood

• Monitor pt for pituitary, thyroid, or adrenal disease

• Check TFTs at baseline and prior to each dose

• Time to onset may be much later; median 11 wks

Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361-1375.

Pituitary gland

Hypothalamus

Thyroid gland

T4 T3

SULTsUGTs

liver

01

T4→T3

T3/TR

rT3,T2inactive

T4/T3-sulfateT4/T3-glucuronide inactive

Excretion

T4 >> T3

02.03


Presenter

Presentation Notes

TFTs, thyroid function tests. Immune‑mediated endocrinopathies can be serious or fatal if not managed correctly. Time to onset may be much later. The average onset in patients treated with ipilimumab was 9 weeks.[1] Low‑dose corticosteroids are recommended, levothyroxine can replace thyroid hormone, and treatment may have to be delayed. Hypophysitis, thyroid disease or abnormal thyroid function tests, and primary adrenal insufficiency have all been reported. The mechanism of injury is not fully understood. Hypophysitis can be permanent but can be managed with hormone replacement. Patients should be monitored for signs and symptoms associated with pituitary, thyroid, or adrenal disease. Symptoms are often nonspecific but may include headache, fatigue, changes in mental status, abdominal pain, and hypotension. Thyroid function tests should be checked at baseline and prior to each dose. TSH is the most sensitive test, but if the patient is symptomatic, consider a full panel including T3, T4, cortisol, and ACTH. Reference 1. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697.


TARGETED THERAPY

BRIM-3: OS with vemurafenib vs DTIC in patients with BRAF V600E-mutant melanoma

OS=overall survival; CI=confidence interval; HR=hazard ratio. McArthur GA, et al. Lancet Oncol 2014;15:323–32.

Vemurafenib(n=295)

DTIC(n=303)

Median OS, months (95% CI) 13.3 (11.9–14.9) 10.0 (8.0–14.0)

Adjusted HR (95% CI) 0.75 (0.60–0.93)

Ove

rall

surv

ival

(%)

100

0

80

60

40

20

01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

295 294 293 285 274 261 244 223 212 198 181 172 153 138 121 95 75 58 37 25 15 7 3 1 1303 275 251 220 196 175 157 142 118 103 90 84 73 68 59 46 32 27 23 13 7 4 0 0 0

VemurafenibDacarbazine

VemurafenibDacarbazine

HR 0.75 (95% Cl 0·60–0·93)p=0.0085

Time from randomisation (months)Number at risk

Genomic Analysis and 3-Year Efficacy and Safety Update of COMBI-d<br />A phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma

Presented By Keith Flaherty at 2016 ASCO Annual Meeting

COMBI-d: PFS and OSa


COMBI-d: Normal LDHa and < 3 Disease Sitesb


Pyrexia managment

• Mild – paracetamol, NSAIDs• Moderate or associated with rigors,

dehydration – withhold dabrafenib/trametinibuntil resolves

• Severe, involving hypotension, renal failure –withhold dabrafenib/trametinibsteroidsonce resolved can safely restart therapy

Australian context

Stage 3/resected stage 4• Adjuvant therapy currently under consideration by PBAC

Stage 4• BRAF mutant – dabrafenib/trametinib or

vemurafenib/cobimetinib on PBS

• BRAF wildtype – pembrolizumab/nivolumab on PBS – Compassionate access to Ipi/nivo combination

Australian context

• Ongoing trials – PD1 +CTLA4SequencingCombination braf/immunotherapyImmunotherapy plus other agents

Case

• 63 year old male• Melanoma removed from shoulder 2013• March 2015 presented with R arm weakness

then seizures• Imaging showed multiple brain mets as well as

lung and mediastinal disease• Bronchoscopy and biopsy confirmed

metastatic melanoma• BRAF wild type

Case 1 cont’d

• Seizures controlled on dex/carbamazepine• Started on pembrolizumab early May 2015• Early June phone call from family – R arm

weakness had worsened, some confusion• Dexamethasone increased to 4mg bd• Pembrolizumab continued• July - arm weakness better, no seizures, dex

reduced to 2mg daily then subsequently ceased

Case 1 cont’d

• Now:– Working in son’s business– No seizures– Back driving– Near complete response on scans

• PET no disease• MRI not quite normal

– Toxicity: mild diarrhea– Treatment ceased

Autoimmune hepatitis

Other toxicities – rash D/T

Other toxicities – rash pembro

Question 1:

• How many people die in Australia each year from melanoma?a) 300b) 1600c) 10000

Answer

• 1600

Question 2:

• What is the 2 year survival for someone with metastatic melanoma treated with immunotherapy?a) 10%b) 30%c) 55%

Answer

• 55%

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