Toxicity from Checkpoint Inhibitors. James Larkin FRCP PhD

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1 Toxicity from Checkpoint Inhibitors James Larkin FRCP PhD

2 Disclosures Research support: BMS, MSD, Novartis, Pfizer Consultancy (all non-remunerated): BMS, Eisai, GSK, MSD, Novartis, Pfizer, Roche/Genentech

3 Checkpoint inhibitors: what are they?

4 Checkpoint inhibitors: what are they?

5 Checkpoint inhibitors: what are they?

6 Checkpoint inhibitors: approval status

7 Checkpoint inhibitors: approval status Not approved for RCC!

8 Checkpoint inhibitors: approval status Not approved for RCC! Anti-CTLA4 ipilimumab melanoma approval 2011 Anti-PD1s pembrolizumab and nivolumab melanoma FDA approval 2014 Nivolumab NSCLC FDA approval March 2015 These and others e.g. MPDL320A, MEDI4736 in trials in multiple tumour types e.g. bladder, H+N In RCC, both anti-pd-1/pdl-1 monotherapy and combination with anti-ctla4 in trials

9 Overall survival (%) Melanoma: pooled OS analysis in 4846 patients Ipi 3 yr OS 21% Schadendorf JCO Time (years)

10 Overall survival (%) Melanoma: pooled OS analysis in 4846 patients Nivo 2 yr OS 48%, n=53 Hodi ASCO 2014 Ipi 3 yr OS 21% Schadendorf JCO Time (years)

11 Overall survival (%) Melanoma: pooled OS analysis in 4846 patients Nivo + ipi 2 yr OS 79%, n=107 Sznol ASCO 2014 Nivo 2 yr OS 48%, n=53 Hodi ASCO 2014 Ipi 3 yr OS 21% Schadendorf JCO Time (years)

12 Are there toxicity differences between anti- CTLA and anti-pd-1/pd-l1? Quantitively, yes i.e. grade 3-4 toxicity in about 15-20% with ipilimumab and 5-10% with anti-pd1 Qualitatively, less so Should we think about the drugs differently? I don t think so Key message about toxicity management: EDUCATION of the patient, their family and all clinicians involved in treatment

13 Before I go any further:

14 Before I go any further: 1) I do not believe there is a clinically significant difference in toxicity profile for any anti-pd1/pd-l1 given as a single agent i.e. nivolumab ~ pembrolizumab ~ MPDL3280A ~ MEDI4736 etc

15 Before I go any further: 1) I do not believe there is a clinically significant difference in toxicity profile for any anti-pd1/pd-l1 given as a single agent i.e. nivolumab ~ pembrolizumab ~ MPDL3280A ~ MEDI4736 etc 2) In general terms I do not think there is any reason to expect significantly different toxicity in different tumour types although patient fitness and comorbidity is obviously relevant

16 Toxicity grade Weber-gram: immune-related adverse events with ipi: kinetics Rash, pruritis Liver toxicity Diarrhoea, colitis Hypophysitis Time (weeks) Ipilimumab Treatment Weber JCO 2012

17 Safety profile of pembrolizumab in melanoma Robert NEJM 2015

18 Safety profile of pembrolizumab in melanoma Robert NEJM 2015

19 Safety profile of nivolumab + ipi in melanoma Postow NEJM 2015

20 Safety profile of nivolumab + ipi in melanoma Postow NEJM 2015

21 Safety profile of nivolumab + ipi in RCC ESMO 2014 Treatment-related select AE categories Category, n (%) N3 + I1 (n = 21) N1 + I3 (n = 23) All Grade 3/4 All Grade 3/4 Endocrinopathy 3 (14.3) 0 8 (34.8) 0 Adrenal insufficiency 1 (4.8) 0 2 (8.7) 0 Hypothyroidism 3 (14.3) 0 6 (26.1) 0 Hyperthyroidism (8.7) 0 Autoimmune thyroiditis (4.3) 0 Gastrointestinal disorder 6 (28.6) 1 (4.8) 9 (39.1) 4 (17.4) Diarrhea 6 (28.6) 1 (4.8) 8 (34.8) 3 (13.0) Colitis 1 (4.8) 0 2 (8.7) 2 (8.7) Hepatic 1 (4.8) 0 9 (39.1) 6 (26.1) AST increased (39.1) 3 (13.0) ALT increased 1 (4.8) 0 9 (39.1) 6 (26.1) Blood bilirubin increased (4.3) 1 (4.3) 8 Hammers ESMO 2014

22 What toxicity should we focus on? Toxicity Diagnosis Treatment Patients sick? Notes Pneumonitis Moderate Moderate Yes Greater impact in NSCLC than other cancers Neuro e.g. Guillain Barre Moderate Difficult Yes Can be prolonged admission; supportive care++ Colitis Easy Difficult Yes Patients can be very sick Endocrine Difficult at times Can be difficult Rarely Pituitary/thyroid/adrenal differential can be complex

23 What toxicity should we focus on? Toxicity Diagnosis Treatment Patients sick? Notes Hepatic Easy Easy Rarely Good algorithms; intense I/S may be needed Skin Easy Easy Rarely Good algorithms Pneumonitis Moderate Moderate Yes Greater impact in NSCLC than other cancers Neuro e.g. Guillain Barre Moderate Difficult Yes Can be prolonged admission; supportive care++ Colitis Easy Difficult Yes Patients can be very sick Endocrine Difficult at times Can be difficult Rarely Pituitary/thyroid/adrenal differential can be complex

24 What toxicity should we focus on? Toxicity Diagnosis Treatment Patients sick? Notes Hepatic Easy Easy Rarely Good algorithms; intense I/S may be needed Skin Easy Easy Rarely Good algorithms Pneumonitis Moderate Moderate Yes Greater impact in NSCLC than other cancers Neuro e.g. Guillain Barre Moderate Difficult Yes Can be prolonged admission; supportive care++ Colitis Easy Difficult Yes Patients can be very sick Endocrine Difficult at times Can be difficult Rarely Pituitary/thyroid/adrenal differential can be complex

25 What toxicity should we focus on? Toxicity Diagnosis Treatment Patients sick? Notes Hepatic Easy Easy Rarely Good algorithms; intense I/S may be needed Skin Easy Easy Rarely Good algorithms Pneumonitis Moderate Moderate Yes Greater impact in NSCLC than other cancers Neuro e.g. Guillain Barre Moderate Difficult Yes Can be prolonged admission; supportive care++ Colitis Easy Difficult Yes Patients can be very sick Endocrine Difficult at times Can be difficult Rarely Pituitary/thyroid/adrenal differential can be complex

26 Lessons from the melanoma experience

27 Lessons from the melanoma experience 1) Education is critical

28 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical

29 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical 3) Early assessment and intervention is critical

30 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical 3) Early assessment and intervention is critical 4) Multi-disciplinary working is critical but

31 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical 3) Early assessment and intervention is critical 4) Multi-disciplinary working is critical but 5) the oncologist needs to lead the team

32 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical 3) Early assessment and intervention is critical 4) Multi-disciplinary working is critical but 5) the oncologist needs to lead the team 6) Good algorithms exist for toxicity management

33 Lessons from the melanoma experience 1) Education is critical 2) Thinking of the diagnosis (e.g. pneumonitis, pituitary failure, Gullain- Barre) is critical 3) Early assessment and intervention is critical 4) Multi-disciplinary working is critical but 5) the oncologist needs to lead the team 6) Good algorithms exist for toxicity management 7) We need to know more about toxicity management; currently steroids are the mainstay but little good quality data to guide

34 Conclusions Anti-PD1/PDL-1 alone very well tolerated Anti-CTLA4 alone more toxicity but manageable Anti-CTLA4 + anti-pd1 has augmented anti- CTLA4-esque toxicity This is probably dose-dependent and the RCC doses (I1 + N3) may be less toxic than the melanoma doses (I3 + N1) for ipi + nivo Toxicity is distinct from targeted agents and cytotoxics, but is manageable

35 Thank you