1. Updates in Immunotherapy Focus on Checkpoint Inhibitors in Oncology
Christopher Campen PharmD BCOP
Greenville Health System – Cancer Institute
Clinical Pharmacist
October 27,2016

2. Disclosures
Advisory board for Taiho Oncology and Eisai

3. Objectives
1. Discuss the mechanisms and indications of immunotherapy agents.
2. Define the principles of immunotherapy toxicities and assess general management strategies for the pharmacist.
3. Describe future ongoing high-interest areas in immunotherapy treatment.
4. Discuss limitations in future use of immunotherapy agents including cost of therapy.

4. The Immune System and Cancer
Immune system design
Cancer evades immune destruction
“hide” or prevent T-cell invasion
Downregulates expression of surface antigens
Overexpression of surface proteins designed to induce immune deactivation
Changes in microenvironment around tumor
Immunotherapy: using the immune system to treat cancer. Accessed 10/4/2016.

5. Innate vs. Adaptive Immunity
Nonspecific defense mechanism
First line of defense
Fast
WBC’s, neutrophils
Adaptive
Antigen-specific immune response
Memory
Slower
B and T cells
Surveillance and cancer
Both innate and adaptive response involved
Goals of immunotherapy

6. T-Cells
Mellman I, et al. Nature. 2011;480:

7. History of Immunotherapy
1997: First mAb for cancer approved, rituximab
2011: CTLA-4 inhibitor approved for melanoma
1976: BCG vaccine for bladder cancer
2008: First cancer vaccine approved for RCC
1796: First use of immunotherapy,
Jenner smallpox vaccine
1992: IL-2 approved for RCC
1863: Connection between immunotherapy and cancer recognized
: PD-1 inhibitors approved for melanoma, squamous NSCLC
1985: Interferon approved
2010: Sipuleucel-T approved for prostate cancer
2016: PD-1 inhibitor approved for cHL
PD-L1 inhibitor approved for UC
Elert E. Calling Cells to Arms. Nature. 2013;504:S2-S3.

8. Patient Case
RJ is a 58 year old male with newly diagnosed metastatic melanoma
BRAF mutation negative
Patient performance status good
Provider recommending treatment
Ipilimumab + nivolumab

9. Immunotherapy Modalities
Checkpoint Inhibitors
Immune Cell-based tx
Therapeutic Antibodies
Treatments
Immune Modulators
Vaccine Therapies

10. Checkpoint Pathway Target checkpoints in immune pathway
Release “brakes” in immune pathway
Target T cells
Approved checkpoint inhibitors
Cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4)
Programmed Cell Death-1 (PD-1)
Programmed Cell Death-1 receptor ligand (PD-L1)

11. Mechanisms TCR = T-Cell Receptor
MHC = Major Histocompatibility Complex
Dizon DS. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology. 2016:

12. FDA Approved Agents (PD-1/PD-L1 Inhibitors)
Nivolumab
Hodgkin Lymphoma
Melanoma
Non Small Cell Lung Cancer
Renal Cell Carcinoma
Pembrolizumab
Non Small Cell Lung cancer
Head/Neck Cancer
Atezolizumab
Urothelial Carcinoma

13. FDA Approved Agents (CTLA-4 Inhibitor)
Ipilimumab
Melanoma
Adjuvant and metastatic

14. Checkpoint Inhibitors
Ipilimumab
Cytotoxic T Lymphocyte-Associated Antigen (CTLA-4)
Ipilimumab 3 mg/kg Q3weeks x 4 doses
Metastatic melanoma - Improvement in median OS
10.1 months vs. 6.4 months with gp100.
Long-term survival improvements in ~25% of patients
Immune toxicities – Black box warnings/REMS
Led to FDA approval of first checkpoint inhibitor in 2011
Hodi FS, et al. N Engl J Med. 2010;363:

15. Melanoma – PD-1 blockade
Ipilimumab Refractory
Versus Chemotherapy
~2-fold improvement in 6-month PFS
First-Line
Versus Ipilimumab
Nearly 2-fold improvement in 6-month PFS
A/E profile
Ribas A et al. Lancet Oncol 2015;
Robert C et al. N Engl J Med 2015;

16. Progression-Free Survival
Ribas A et al. Lancet Oncol 2015;

17. Ipilimumab/Nivolumab
Ipilimumab x 4 doses + nivolumab maintenance vs. nivolumab vs. ipilimumab – Metastatic Melanoma
Phase III, ~315 patients each arm
Best Overall Response
Nivolumab (%)
Nivo + Ipi (%)
Ipilimumab (%) CR
8.9
11.5
2.2 PR
34.8
46.2
16.8 SD
10.8
13.1
21.9 PD
37.7
22.6
48.9
Larkin J, et al. N Engl J Med. 2015;371:23-34.

18. Progression-free Survival
Larkin J, et al. N Engl J Med. 2015;371:23-34.

19. Combination Blockade Putting results into perspective for melanoma
PFS 6 years ago versus now
Significant toxicities
Future directions to maintain/improve responses + mitigating toxicities
Clear choice for patients? Stratification?

20. Patient Case
RJ is a 58 year old male with newly diagnosed metastatic melanoma
BRAF mutation negative
Patient performance status good
Provider recommending treatment
Ipilimumab + nivolumab
Clinical checks for pharmacists?

21. Non-Small Cell Lung Cancer
Pembrolizumab
Metastatic NSCLC
Refractory to platinum agent, PD-L1+
2700 patients screened
1475 PD-L1 positive
633 > 50% %
~1000 patients assigned to treatment
Pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, Docetaxel
Herbst R, et al. Lancet 2016;387:

22. Pembrolizumab - NSCLC Overall Survival Analysis Adverse event analysis
OS 10.4 months (pembro 2 mg/kg) vs. 8.5 months (docetaxel), HR 0.71 CI
Hazard Ratio Analysis by PD-L1
PD-L1 1-49: ( )
PD-L1 50+: 0.53 ( )
Adverse event analysis
Herbst R, et al. Lancet 2016;387:

23. Non-Small Cell Lung Cancer
Nivolumab
Metastatic NSCLC
Refractory to platinum agent, did NOT have to be PD-L1+
Nivolumab vs. docetaxel Q3w
Overall survival 12.2 months vs. 9.4 months respectively
Progression-free survival 2.3 mo vs. 4.2 mo respectively
Borghaei, et al. N Engl J Med 2015;373:

24. Overall Survival
Borghaei, et al. N Engl J Med 2015;373:

25. Metastatic NSCLC – First-Line Treatment
PD-L1 > 50% staining
No mutations in EGFR/ALK
Pembrolizumab vs. investigator choice platinum combination
1653 patients eval for PD-L1, 500 > 50% TPS PD-L1
305 patients randomized
Median PFS 10.3 months vs. 6 months respectively
OS at 6 months 80.2% vs. 72.4%
Immune related adverse events ~30% of patients
Not FDA approved yet for this indication
Reck M, et al. N Engl J Med 2016;epub ahead of print October 9.

26. Progression-free Survival
Reck M, et al. N Engl J Med 2016;epub ahead of print October 9.

27. Managing Toxicities Unique spectrum Not all immunotherapies are equal
Combination immunotherapy increases toxicity
Important to intervene early
Don’t be afraid to stop immunotherapy

28. Toxicities Dermatitis (rash) Colitis Hepatitis Pneumonitis
Endocrinopathies
Hypothyroidism
Hypophysitis

29. Monitoring Thyroid Function Tests Hepatic Function Tests
Serum Creatinine
Rash
Diarrhea
Changes in lung function (SOB)

30. PD-1/PD-L1 Inhibitors (Nivolumab for reference)
Adverse Event
Any Grade (%)
Grade 3/4 (%)
Dermatitis
25.9
0.6
Diarrhea
19.2
2.2
AST/ALT ↑
3.8 1
Dyspnea
4.5
0.3
Hypothyroidism
8.6
Tx Discontinuation
7.7
Larkin J, et al. N Engl J Med. 2015;371:23-34.

31. Ipilimumab 3 mg/kg Adverse Event Any Grade (%) Grade 3/4 (%)
Dermatitis
32.8
1.9
Diarrhea
33.1
6.1
AST/ALT ↑ ~4
~1.5
Dyspnea
4.2
Hypothyroidism
Tx Discontinuation
14.8
Larkin J, et al. N Engl J Med. 2015;371:23-34.

32. Ipilimumab 10 mg/kg Adverse Event Any Grade (%) Grade 3/4 (%)
Dermatitis 38 1
Diarrhea 39 10
AST/ALT ↑ 16 5
Dyspnea NR
Hypothyroidism 9
Hypophysitis 13 6
Tx Discontinuation 52
Eggermont A et al. Lancet Oncol 2015; 16: 522–30.

33. Nivolumab/Ipilimumab
Adverse Event
Any Grade (%)
Grade 3/4 (%)
Dermatitis
40.3
4.8
Diarrhea
44.1
9.3
AST/ALT ↑
~17 ~8
Dyspnea
10.2
0.6
Hypothyroidism 15
0.3
Tx Discontinuation 36
Larkin J, et al. N Engl J Med. 2015;371:23-34.

34. Weber J et al. J Clin Oncol 2012:2691-97.

35. Managing Toxicities Based on severity of the toxicity
General rules for management
Moderate (grade 2), hold checkpoint inhibitor and resume when grade 1 or less.
Severe/life threatening (grade 3/4) non-rash, discontinue treatment. High dose steroids.
Use topical treatments/supportive care when indicated
Postow MA ASCO educational book

36. Steroids Steroids are vital in blunting the effects of immunotherapies
Dosing 1-2 mg/kg/day prednisone
Effective, fast
Doses often cannot be titrated off quickly
Opportunistic infections – Consider PJP prophylaxis in patients on steroids > 4 weeks at doses > prednisone 20 mg/day
Postow MA ASCO educational book

37. Patient Case RJ is a 58 year old male with metastatic melanoma
Completed 3 cycles of treatment
Ipilimumab + nivolumab
Wife calls clinic, RJ experiencing 8-10 stools a day for the last 5 days
Patient called after 2 days, told to take loperamide
Nurse asks for guidance

38. Patient Case RJ is a 58 year old male with metastatic melanoma
Patient now hypotensive in clinic
Sent to hospital for management
Stool tests negative, presumed to be colitis
Treatment options?

39. Treating A/E’s Refractory to Steroids
Continue supportive care
Increase steroid dose
Add infliximab 5 mg/kg every 2 weeks
Postow MA ASCO educational book

40. Key Points
Most patients respond to steroids and removal of offending immunotherapy
Do not delay
Taper steroids SLOW
Steroids do NOT blunt the effectiveness of checkpoint inhibitors
Immune A/E’s do not appear to correlate with efficacy
Stopping treatment is OK!!!

41. Limitations Not all studies have been successful
Only a small percentage of certain tumors are infiltrated by effector T-cells
50% of melanomas
20-30% renal cell carcinoma
20% of non small cell lung cancer
<20% colorectal tumors (mostly MSI high)

42. Limitations Negative studies Nivolumab first line treatment for NSCLC
Phase III, 541 patients
Nivolumab 3 mg/kg Q2weeks versus chemotherapy
Excluded EGFR and ALK mutations
PD-L1 expression 5% cutoff (423 patients)
PFS 4.2 months nivolumab vs. 5.9 months chemo (p=0.25)
OS 14.4 vs 13.2 months (p = NS)
Accessed

43. Limitations Negative studies
Combination chemotherapy +/- ipilimumab for first line treatment of SCLC
Phase III, 1,132 patients
Ipilimumab 10 mg/kg Q3weeks x 4 doses
Median OS 11 months with combo chemo-immunotherapy vs months immunotherapy alone
High rates of AE’s
High rates of treatment discontinuation
Reck M, et al. J Clin Oncol epub ahead of print July 25,2016.

44. Limitations Biomarkers No perfect biomarker
Responses can occur in patients with no/low PD-L1 staining
Responses enriched high PD-L1 staining
Biomarkers to stratify treatment may go beyond just immunologic biomarkers
Molecular, genomic

45. Immunoscore
Method to define the level of immune cell infiltration into cancer cells
Density measurement CD8+ and CD3+ T Cells center/periphery
ASCO 2016 presentation
~2700 colon cancer patients, stage I-III
Overall survival and time to recurrence improved in immunoscore high vs. low patients
Immunotherapy study implications
May eventually add on to the TNM classification – TNM-I
Galon J, et al. ASCO Abstract 3500.

46. Limitations
Cost
PD-1/PD-L1 x 1 year (approved doses) – approx $150,000-$180,000
Ipilimumab 3 mg/kg x 4 doses – approx $160,000
Ipilimumab/nivolumab x 1 year – approx $300,000
Ipilimumab 10 mg/kg adjuvant treatment – ~125,000 PER DOSE or ~1.8 million for the entire 3 year course
Accessed

47. Cost
Many studies now using PD-1/PD-L1 dosing beyond FDA approved dosing
Studies mostly positive, but at what cost?
Impact on society – 1.6 million cancer cases each year
Accessed

48. Future Research Biomarkers/Immune scoring
PD-1/PD-L1 blockade studies in additional cancers
Multiple myeloma, GI cancers, lymphoma, breast cancer
When to stop treatment
Traditionally at progression
Combination checkpoint inhibition
Targeting activating T-Cell receptors
Induction of T-cell infiltration in low immunogenic tumor types
Vaccine based therapies, stimulate, ie light the fire

49. T-Cells
Mellman I, et al. Nature. 2011;480:

50. Conclusion Checkpoint inhibition is just the beginning
Pharmacists play a key role in management of immunotherapy
Work with staff for education and development of tools to assess immunotherapy A/E’s
For severe immunotherapy a/e’s – Steroids
It is not a race to stop steroids