The Royal Marsden

1

Advances in the treatment of melanoma and kidney cancer

Dr Samra TurajlicConsultant Medical Oncologist,

The Royal Marsden

Group Leader, the Francis Crick

Institute

Melanoma: Molecularly distinct diseases arising from the same cell of origin (melanocyte) in different anatomical sites

Cutaneous: chronically and intermittently sun-exposed skin

(BRAF 40%, NRAS 20%)

Acral (KIT 15%, BRAF 15%)

Ocular (GNAQ, GNA11, BAP1, SF3B1)

Mucosal (KIT 20%, NRAS 15%)

Gastrointestinal

Genitourinary

Sinonasal

Melanoma: Survival is linked to stage

Balch JCO 2009

Melanoma: Stage IV (metastatic) disease historical survival: median 6-9 monthsLargely resistant to chemotherapy

Chapman NEJM 2011

Melanoma: genetic discovery informs the first successful targeted therapy

Chapman NEJM 2011

Melanoma: responses to BRAF targeting excellent but often short-lived

Median progress-free survival ~6 months

Arozarena and Wellbrock 2017

Melanoma: Mechanism of resistance to BRAF inhibitors- dominated by reactivation of the signaling pathways downstream of BRAF gene

Trial

Progression Free Survival

medians

Dabrafenib + trametinibvs vemurafenib

11.4 vs 7.3 mos

HR 0.56, p<0.001

Dabrafenib + trametinibvs dabrafenib

9.3 vs 8.8 mos

HR 0.75, p=0.03

Vemurafenib + cobimetinibvs vemurafenib

9.9 vs 6.2 mos

HR 0.51, p<0.0001

Encorafenib + binimetinibvs vemurafenib

14.9 vs 7.3 mos

HR 0.54, p<0.0001

Long NEJM 2014, Larkin NEJM 2014, Robert NEJM 2015, Dummer TLO 2018

Melanoma: Combined BRAF & MEK inhibitors improve on BRAF inhibitors aloneNew standard of care

BRAFi

BRAFi and MEKi

Flaherty et al NEJM 2013

Mathematical Model: Most radiographically detectable lesions harbour at least 10 resistant subclones….

Melanoma: Resistance to targeted treatment almost inevitable in the metastatic setting-mechanisms pre-exist and are selected under the selective pressure of therapy

Resistant mutation

Treatment

Turajlic and Swanton, Nat Rev Drug Discov. 2017

Long NEJM 2017

Melanoma: Benefit of targeted therapy in the adjuvant setting- resistance not inevitable in this setting

BRAFi and MEKi

Interferon

+++

Immune stimulation

Interleukin 2

Harnessing the immune system to treat melanoma:The advent of immune checkpoint blockade

Interferon

+++

CTLA-4

- - -

Immune regulation

Immune stimulation

PD-1

Interleukin 2

e.g.

e.g.

APC T cell

MHC TCR

How does immune regulation function- Step 1: T cell activation

APC T cell

PD-1

B7-1 (CD80)

PD-L1

PD-L2

CD40 CD40L

CD137

OX40

CD137L

OX40L

LAG-3

MHC

CD28 ActivationB7-2 (CD86)

B7-1 (CD80) CTLA-4 Inhibition

TCR

Inhibition

Inhibition

Activation

Activation

Activation

Inhibition

• Immune checkpoints limit or ‘check’ an ongoing immune response

• Prevent damage to the healthy tissues

• Magnitude and quality of a T-cell response is regulated by a balance of activating and inhibitory signals

How does immune regulation function-Step 2: balance of activating and inhibitory signals

APC T cell

PD-1

B7-1 (CD80)

PD-L1

PD-L2

CD40 CD40L

CD137

OX40

CD137L

OX40L

LAG-3

MHC

CD28 ActivationB7-2 (CD86)

B7-1 (CD80) CTLA-4 Inhibition

TCR

Inhibition

Inhibition

Activation

Activation

Activation

Inhibition

CTLA4 blocking antibody:

Ipilimumab

PD1 blocking antibodies:

Nivolumab

Pembrolizumab

PDL1 blocking antibodies:

Atezolizumab

Exploitation of immune checkpoints for anti-tumour immune response

Escalating number of new indications for the use of Immune Checkpoint Inhibitors

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Melanoma: The tail on the curve- immune checkpoint blockade may be a curative therapy?

17

Schadendorf et al. JCO 2015

Patients with metastatic melanoma treated with ant-CTLA4- 10 year follow up

Melanoma: Nivolumab + ipilimumab combination (PD1 and CTLA4 blockade)

2019: Overall survival >50% at 5 years cf2009: Overall survival 10-20% at 5 years

Melanoma: challenging areas - Brain Metastases, immunotherapy is effective

Tawbi NEJM 2018

Immunotherapy is associated immune-related toxicity

Wolchok NEJM 2017

▪ Uveitis▪ Conjunctivitis▪ Scleritis, episcleritis▪ Blepharitis▪ Retinitis

Eye

1. Michot JM, et al. Eur J Cancer. 2016;54:139-148.2. Champiat S, et al. Ann Oncol. 2016;27(4):559-574.

DRESS, drug reaction with eosinophilia and systemic symptoms; GI, gastrointestinal; imAEs, immune-mediated adverse events.

▪ Encephalitis▪ Guillain–Barré▪ Myelopathy▪ Meningitis▪ Myasthenia gravis▪ Neuropathy

Neu

rolo

gica

l

▪ Pneumonitis▪ Interstitial lung disease▪ Pleuritis▪ Sarcoid-like granulomatosisR

esp

irat

ory

▪ Colitis▪ Ileitis▪ Pancreatitis▪ Gastritis

Gas

tro

-in

test

inal

▪ Haemolytic anaemia▪ Thrombocytopenia▪ Neutropaenia▪ Haemophilia

Blo

od

▪ Hyperthyroidism▪ Hypothyroidism▪ Hypophysitis▪ Adrenal insufficiency▪ Diabetes

End

ocr

ine

▪ Arthritis▪ Dermatomyositis

Mu

sculo

-ske

letal

▪ Hepatitis

Hep

atic

▪ Nephritis▪ Renal failure

Ren

al

▪ Rash▪ Pruritus▪ Psoriasis▪ Vitiligo▪ DRESS▪ Stevens–Johnson syndrome▪ Toxic epidermal necrolysis

Skin

▪ Myocarditis▪ Pericarditis▪ Vasculitis

Card

io-

vascul

ar

Immune-related toxicity can affect any organ tissue and requires careful multi-disciplinary management and follow-up

RMH leading on informing the practical management guidelines nationally and internationally

Translational protocol in development at Royal Marsden:

EXACT – understanding immunE related toXicities by multifACeT profiling

Chief Investigator: Samra Turajlic, EXACT collaborators, clinical fellow Laura Boos

C1 C2 C3 C4baselineTOXICITY

Faecal calprotectinStool microbiome analysisBlood markers

Faecal calprotectinStool microbiome analysisBlood markers

All baseline assessments repeatedBlood Markers

Faecal calprotectin

Understanding the mechanisms that underpin different Immune-related toxicities will help their management

Melanoma: Adjuvant immunotherapy decreases the risk of relapse for stage 3 disease

Ipillimumab

Nivolumab

Weber NEJM 2017

Melanoma- Challenges for Immunotherapy

• Duration of therapy: how much is needed?

• Side effects for combination therapy (Effect on fertility may be particularly relevant for

many of our patients in the adjuvant setting)

• Neoadjuvant therapy showing great early promise- will it be durable?

• No benefit from immunotherapy in 40% of patients….new targets and combinations

needed→ extensive programme at RMH Skin Unit to understand the mechanisms of

resistance (Melanoma TRACERx and PEACE studies)

Excise tumor

clinical site to CMO

Thaw andinfuse LN-144,

followed by IL-2 administration

Fragmentation

Expansionex vivo

ex vivo culture

IL-2 +

OKT3

Co-culture TILand feeder cells

Rapid Expansion (REP) 11 days

Tumor Fragment Culture (Pre-REP) 11 days

+ IL-2

Cryopreserved TIL infusion

product

Harvest

NMA-LD preconditio

ning therapy

Melanoma- latest advances, Adoptive Cell Therapy

Melanoma- latest advances, Adoptive Cell Therapy

41% objective response rate in heavily pre-treated patients

Ongoing studies at RMH

Clear Cell 75% (ccRCC)Papillary 15%

Collecting duct<1%Medullary <1%

Chromophobe 5%Oncocytoma <1%

Proximal tubule

Distal tubule

Cortex

Medulla

Renal Cell Carcinoma: distinct histological subtypes diseases arising from the nephron

ccRCC: Survival is linked to stage

• ~30% distant relapse after localized management

• ~30% present with de-novo metastatic disease

• Metastatic latency highly variable (e.g. pancreatic very late)

• Clinical progression trajectory also highly variable (e.g. low volume lung mets)

Site Incidence (%)

Lung 50-60%

Lymph node 30-40%

Liver 30-40%

Bone 30-40%

Adrenal 20%

Contralateral kidney

10%

Brain 5%

ccRCC: Two contexts of metastatic disease

ccRCC: Variable outcomes from systemic treatment of metastatic disease

MSKCC Criteria1

Treated with first line interferon-alfa

Prognostic factors

Prognostic group Median OS

Time to systemic therapy (<1 yr)

29.6 months

95%CI 20.9-37.8mPerformance status (KPS <80%)

LDH(>1.5x ULN)

13.8 months95%CI 12.4-15.9m

Anaemia(<LLN) 4.9 months

95%CI 4.3-6.3mHypercalcaemia(>ULN)

IMDC (Heng’s) Criteria2,3

Treated with first-line TKI

Prognostic factors Prognostic group Median OS

Time to systemic therapy (<1 yr) 43.2 months

95%CI 31.4-50.1mPerformance status (KPS <80%)

Anaemia(<LLN) 22.5 months

95%CI 18.7-25.1mHypercalcaemia(>ULN)

Neutrophilia(>ULN) 7.8 months

95%CI 6.5-9.7mThrombocytosis(>ULN)

ccRCC: Variable outcomes associate with distinct patterns of tumour evolution

ccRCC: Function inactivation of VHL gene is a hallmark →pseudohypoxia→increase in vascular endothelial growth factor (VEGF)

Lindgren, D., J. Sjolund, and H. Axelson, Tracing Renal Cell Carcinomas back to the Nephron. Trends Cancer, 2018. 4(7): p. 472-484.

cRCC: VEGF pathway is a critical therapy target

CA Cancer J Clin. 2017 Nov;67(6):507-524. doi: 10.3322/caac.21411. Epub 2017 Sep 29. Treatment of renal cell carcinoma: Current status and future directions. Barata PC1, Rini BI2.

ccRCC: VEGF inhibition- Sunitinib

1st line anti-VEGF vs cytokineProgression free survival- 11 vs 5 months (HR0.42)

Overall survival update (2009, JCO)- 26.4 vs 21.8 months (HR0.82, p=0.51)

“Overall survival differed according to MSKCC risk groups (favorable > intermediate > poor risk) for patients treated on each arm of the trial”

J Clin Oncol. 2009 Aug 1;27(22):3584-90. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. Motzer RJ1,

ccRCC: Pazopanib versus Sunitinib

Pazopanib demonstrated PFS benefit in phase III study (Sternberg et al, JCO 2010)

Efficacy and safety 1st line studyCOMPARZ study

Progression free survival & overall survival- non-inferior compared to sunitinib (HR1.05)- similar compared to sunitinib (HR0.91)

Quality of life scores favoured Pazopanib

Potent selective 2nd generation VEGF inhibitor

- Prior sunitinib / bev + INFa / temirolimus/ cytokine based

- PFS 6.7m vs 4.7m (HR 0.67)- ORR: 19 vs 9% in favour of axitinib

(p=0.0001)- Median duration of response:11 vs

10.6m- Less toxic, discontinuation rate 4 vs 8%- Benefit across pre-specified subgroups

(previous therapy)

ccRCC: new generation VEGF inhibitors- Axitinib

Multi-kinase inhibitor; post 1 or more VEGF-inhibitor

Overall survival- Median 21.4 vs 16.5 months (HR 0.66)

Progression free survival- Median 7.4 vs 3.9 months (HR 0.51)

Objective response rate- 17% vs 3%

Grade 3/4 toxicity rates- 39% vs 40%

ccRCC: multi-kinase inhibitors- Cabozantinib

1st line combination vs sunitinibMSKCC risk groups (n=1096)

• Poor risk 38.5% (n=422)

• Intermediate risk 39% (n=425)

• Favourable risk 22.7% (n=249)

Overall survival- median CPI not reached vs 26m sunitinib (HR0.63)Objective response rate 42% vs 27%

Exploratory analysis – favourable risk group did better on sunitinib

ccRCC: Nivolumab + ipilimumab combination (PD1 and CTLA4 blockade)

Keynote 426 – pembrolizumab plus axitinib vs sunitinib

• OS benefit – HR0.53 (median not reached)

• Response rate 59.3% vs 35.7%

• Benefit in PD-L1 +/- subgroups

Rini et al, NEJM 2019

ccRCC: what about combining VEGF inhibition and immunotherapy?

Immotion 151 - atezolizumab alone or in combination with bevacizumab versus sunitinib

N= 305

Co-primary endpoints: PFS in PD-L1+ population / OS in ITT population

Rini et al, The Lancet 2019

ccRCC: what about combining VEGF inhibition and immunotherapy?

ccRCC: Evolving treatment landscape

1. Hsieh, J.J., et al., Renal cell carcinoma. Nat Rev Dis Primers, 2017. 3: p. 17009.

Ipilimumab + Nivolumab

AntiPD1/PDL1 + anti-VEGF

ccRCC: Evolving treatment landscape- but how to choose the right therapy for each patient?

• APREDICT

A Phase II Study of Axitinib in Patients with Metastatic Renal Cell Cancer Unsuitable for Nephrectomy

• ADAPTeR

A Study of Anti-PD1 (Nivolumab) Therapy as Pre- and Post-operative Therapy in Metastatic Renal Cell Cancer

ccRCC: Evolving treatment landscape- biomarker research at the RMH

Analyses led by Lewis Au

• Scientific progress has laid the foundations for the recent systemic

therapeutic revolution in melanoma and renal cancer

• The role of surgery is changing too

• Several major challenges still remain, notably in refractory populations,

bad biology disease, side effect management and individualisation of

treatment

• Many exciting approaches under evaluation

• Continued engagement in research and clinical trials vital for further

progress

Summary

Acknowledgements

Our patients and their families

Melanoma and Renal Clinical Trials Team, Royal Marsden, led by Kim Edmonds

James Larkin and Lisa Pickering

Friends and colleagues in the UK and internationally in the clinic, academia, industry and advocacy groups

My lab at the Crick institute

The Royal Marsden

Thank you

Samra.Turajlic@rmh.nhs.uk

www.royalmarsden.nhs.uk/private