1. Image: https://www.shutterstock.com/search/antibody

2. this activity possible.
Educational Grants
MD Anderson would like
to acknowledge
Pfizer and EMD Serono,
who helped to make
this activity possible.

3. Mechanism of Action of Immune Checkpoint Inhibitors
Anti-CTLA-4 Pathway
Anti-PD-1/PD-L1 Pathway
Adapted from Soularue et al. Gut For educational purposes only.

4. Immunotherapy in Bladder Cancer

5. FDA-Approved Immunotherapies for Bladder Cancer
PD-L1 Antibodies
Atezolizumab
Avelumab
Durvalumab
PD-1 Antibodies
Nivolumab
Pembrolizumab
FDA = US Food and Drug Administration.

6. KEYNOTE-045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
Overall Survival
PFS
KEYNOTE-045 = A Study of Pembrolizumab vs Paclitaxel, Docetaxel, or Vinflunine for Participants with Advanced Urothelial Cancer; PFS = progression-free survival.
Bellmunt et al. N Engl J Med. 2017; 376: For educational purposes only.

7. IMvigor211: Atezolizumab vs Chemotherapy in Patients with Platinum-Treated Locally Advanced or Metastatic Urothelial Carcinoma
IMvigor211 = A Study of Atezolizumab Compared with Chemotherapy in Participants with Locally Advanced or Metastatic Urothelial Bladder Cancer.
Powles T et al. Lancet. 2018;91: For educational purposes only.

8. JAVELIN Solid Tumor Study: Avelumab in Metastatic Urothelial Carcinoma after Platinum Failure
ORR of 17% at ≥6 months of follow-up
Grade ≥3 treatment-related AE frequency was low (8%) and similar to other agents within the class
AE = adverse event; JAVELIN Solid Tumor Study = Avelumab in Metastatic or Locally Advanced Solid Tumors; ORR = objective response rate.
Patel et al. Lancet Oncol. 2018;19:51-64.

9. Study 1108: Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma
Antitumor Activity of Durvalumab per Blinded Independent Central Review in the Urothelial Carcinoma Cohort, Including the ≥2L Postplatinum Subgroup
CR = complete response; DoR = duration of response; PR = partial response.
Powles T et al. JAMA Oncol. 2017;3:e For educational purposes only.

10. IMvigor 210: Atezolizumab in Platinum-Treated Locally Advanced or Metastatic Urothelial Carcinoma
n (%)
IRF ORR, % (95% CI)
CR, %
PD-L1 Status
IC2/3
100 (32)
27 (19, 37)* 8
IC1/2/3
208 (67)
18 (13, 24)* 5
All
311 (100)
15 (11, 20)* 4
Poor Prognostic Factors
Visceral mets
243 (78)
10 (7, 15) 1
Liver mets
97 (31)
6 (2, 13)
ECOG PS 1
193 (62)
10 (6, 15) 2
Hb <10 g/dL
68 (22)
9 (3, 18)
*P <.01.
ECOG PS = Eastern Cooperative Oncology Group Performance Status; Hb = hemoglobin level; IC1/2/3: = PD-L1 tumor-infiltrating immune cell status; IMvigor 210 = A Study of Atezolizumab in Participants with Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 2); IRF = independent review facility; mets = metastases.
Data from Hoffman-Censits et al. J Clin Oncol. 2016;34(suppl 2):355.

11. KEYNOTE-045: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
At 2-year follow-up:
ORR was higher with pembrolizumab vs chemotherapy (21.1% vs 11.0%).
Median OS was longer with pembrolizumab vs chemotherapy (10.3 vs 7.3 months; HR = 0.70).
OS benefit seen in all PD-L1 expression subgroups.
HR = hazard ratio; OS = overall survival.
Bellmunt J et al. J Clin Oncol. 2018;36(suppl 6):410.

12. Nivolumab in Metastatic Urothelial Carcinoma after Platinum Therapy (CheckMate 275): A Multicenter, Single-Arm, Phase II Trial
Confirmed objective response was achieved in:
28.4% of patients with PD-L1 expression ≥5%
23.8% of patients with PD-L1 expression ≥1%
16.1% of patients with PD-L1 expression ≤1%
Total (n = 265)
Confirmed objective response
52 (19.6%; 95%; CI 15.0–24.9)
Best overall response
6 (2%)
Partial response
46 (17%)
Stable disease
60 (23%)
Progressive disease
104 (39%)
Unable to determine
49 (18%)
Time to response, months
1.87 (1.81–1.97)
Duration of response, months
NR (7.43–NR)
NR = not reached.
Sharma et al. Lancet Oncol. 2017;18: For educational purposes only.

13. Immunotherapy in Renal Cancer

14. CheckMate 025: Nivolumab vs Everolimus in Advanced RCC
CheckMate 025 = Study of Nivolumab vs Everolimus in Pretreated Advanced or Metastatic Clear-cell RCC; RCC = renal cell carcinoma.
Motzer et al; CheckMate 025 Investigators. N Engl J Med. 2015;373: For educational purposes only.

15. CheckMate 025: Nivolumab vs Everolimus in Advanced RCC
Motzer et al; CheckMate 025 Investigators. N Engl J Med. 2015;373: For educational purposes only.

16. CheckMate 214: Nivolumab plus Ipilimumab vs Sunitinib in Advanced RCC
Subgroup Analysis of OS Among IMDC Intermediate- and Poor-Risk Patients
CheckMate 214 = Nivolumab Combined with Ipilimumab vs Sunitinib in Previously Untreated Advanced or Metastatic RCC; IMDC = International Metastatic RCC Database Consortium.
Motzer RJ et al. N Engl J Med. 2018;378: For educational purposes only.

17. Emerging Immunotherapy Combinations in Renal Cancer

18. JAVELIN Renal 101: Avelumab plus Axitinib in Previously Untreated RCC
PD-L1+ Group
(N = 560)
Overall Population
(N = 886)
Avelumab + Axitinib
(N = 270)
Sunitinib
(N = 290)
(N = 442)
(N = 444)
Median PFS per IRC, Months
13.8
7.2
8.4
Benefit vs sunitinib (HR; P value)
0.61;
P <.0001 –
0.69;
P = .0001
ORR per IRC, % 55 26 51
Motzer et al. Ann Oncol. 29:(suppl 8)2018:VIII24: Abstract LBA6 PR.

19. JAVELIN Renal 101: Avelumab plus Axitinib in Previously Untreated RCC
PD-L1+ Group
(N = 560)
Overall Population
(N = 886)
Avelumab + Axitinib
(N = 270)
Sunitinib
(N = 290)
(N = 442)
(N = 444)
Best overall
response per IRC, % CR 4 2 3 PR 51 23 48 24
Stable disease 27 43 30 46
Progressive disease 11 22 12 19
Not evaluable 7 6 8
Motzer et al. Ann Oncol. 29:(suppl 8)2018:VIII24: Abstract LBA6 PR.

20. JAVELIN Renal 101: Avelumab plus Axitinib in Previously Untreated RCC
Overall Population
(N = 886)
Avelumab + Axitinib
(N = 442)
Sunitinib
(N = 444)
Grade ≥3 TEAEs
71.2%
71.5%
TRAEs leading to
discontinuation of all study drugs 4% 8%
Motzer et al. Ann Oncol. 29:(suppl 8)2018:VIII24: Abstract LBA6 PR.

21. JAVELIN Renal 101: Avelumab plus Axitinib in Previously Untreated RCC
PD-L1+ Group
(N = 560)
Overall Population
(N = 886)
Avelumab + Axitinib
(N = 270)
Sunitinib
(N = 290)
(N = 442)
(N = 444)
Best overall
response per IRC, % CR 4 2 3 PR 51 23 48 24
Stable disease 27 43 30 46
Progressive disease 11 22 12 19
Not evaluable 7 6 8
Motzer et al. Ann Oncol. 29:(suppl 8)2018:VIII24: Abstract LBA6 PR.

22. Emerging Combinations in RCC: Pembrolizumab plus Axitinib
Phase III KEYNOTE-426 (NCT ):
Safety and efficacy of pembrolizumab in combination with axitinib vs sunitinib monotherapy as a first-line treatment for patients with advanced/metastatic RCC
Combination therapy resulted in significant improvements in OS, PFS, and ORR.
Results for OS, PFS, and ORR were consistent regardless of PD-L1 expression and across all risk groups.
Merck’s Pembrolizumab in Combination with Pfizer’s Axitinib Significantly Improved OS and PFS as First-Line Therapy for Advanced or Metastatic RCC [press release]. Kenilworth, NJ: Merck & Co Inc; October 18, 2018.

23. Safety and Efficacy of Pembrolizumab in Combination with Axitinib in Patients with Advanced RCC
Phase Ib study of 52 treatment-naïve patients
Combination efficacy:
ORR: 73.1%
mPFS: 20.9 months
CR: 7.7%
PR: 65.4%
Disease stability: 15.4%
Combination safety
No unexpected toxicities observed
Most common (≥10%) grade ≥3 all-causality AEs included hypertension (23%), diarrhoea (10%) and fatigue (10%)
mPFS = median PFS.
Atkins et al. J Clin Oncol. 2018;36(6 suppl): Abstract 579.

24. Lenvatinib plus Pembrolizumab in Patients with RCC
Phase III CLEAR study ongoing
Results anticipated in 2020
Phase Ib/II study of 30 patients
Combination efficacy:
mPFS: 13.8 months
ORR: 63.3%
Treatment-naïve patients: 83%
Combination safety:
Grade 3/4 AE rate: 70%
Discontinuation rate: 13%
Atkins et al. J Clin Oncol. 2018;36(6 suppl): Abstract 579.

25. Immunotherapy in Lung Cancer

26. FDA-Approved Immunotherapies for Lung Cancer
2015
March 4, 2015
Nivolumab for second-line squamous NSCLC
(CheckMate 017 and CheckMate 063)
October 2, 2015
Pembrolizumab for second-line squamous and nonsquamous PD-L1+ NSCLC
(KEYNOTE-010)
October 9, 2015
Nivolumab for second-line nonsquamous NSCLC
(CheckMate 057)
2016
October 18, 2016 Atezolizumab for second-line NSCLC
(OAK and POPLAR)
October 24, 2016 Pembrolizumab for first-line PD-L1+ NSCLC
(KEYNOTE-024 and KEYNOTE-001)
2017
May 10, 2017 Pembrolizumab plus chemotherapy for first-line nonsquamous NSCLC
(KEYNOTE-189)
2018
February 16, 2018
Durvalumab for stage 3 unresectable NSCLC
(PACIFIC)
August 17, 2018
Nivolumab for metastatic SCLC
(CheckMate 032)
October 30, 2018
Pembrolizumab plus chemotherapy for first-line squamous NSCLC
(KEYNOTE-407)
December 6, 2018
Atezolizumab plus chemotherapy for first-line nonsquamous NSCLC
(IMpower 150)

27. KEYNOTE-001: Pembrolizumab as First-Line Therapy for Patients with PD-L1+ Positive Advanced NSCLC
In patients with PD-L1 TPS ≥50%, 24-month OS was higher (61%) than the overall population (44%).
KEYNOTE-001 = Study of Pembrolizumab in Participants with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or NSCLC; NSCLC = non-small cell lung cancer; TPS = tumor proportion score.
Hui et al. Annal Oncol. 2017;28:874–881. For educational purposes only.

28. KEYNOTE-024: Pembrolizumab vs Chemotherapy for PD-L1–Positive NSCLC
Rate of OS at 6 months
Pembrolizumab: 80.2%
Chemo: 72.4%
Response rate
Pembrolizumab: 44.8%
Chemo: 27.8%
KEYNOTE-024 = Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants with Metastatic NSCLC.
Reck M et al; KEYNOTE-024 Investigators. N Engl J Med. 2016;375: For educational purposes only.

29. KEYNOTE-189: Pembrolizumab plus Chemotherapy in Metastatic NSCLC
12-Month OS (%)
Pembrolizumab Combination
Chemotherapy
Combination
TPS (%)
<1
61.7
52.2
1–49
71.5
50.9
≥50
73.0
48.1
KEYNOTE-189 = Study of Pemetrexed + Platinum Chemotherapy with or Without Pembrolizumab in Participants with First Line Metastatic Nonsquamous NSCLC.
Gandhi et al. N Engl J Med. 2018;378:

30. KEYNOTE-407: Pembrolizumab plus Chemotherapy for Squamous NSCLC
KEYNOTE-407 = A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy with or Without Pembrolizumab in Adults with First Line Metastatic Squamous NSCLC.
Paz-Ares L et al. N Engl J Med. 2018;379: For educational purposes only.

31. Immunotherapy in Melanoma

32. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Ipi = ipilimumab.
Hodi et al. N Engl J Med. 2010;363: For educational purposes only.

33. KEYNOTE-006: Pembrolizumab vs Ipilimumab in Advanced Melanoma
KEYNOTE-006 = Study to Evaluate the Safety and Efficacy of 2 Different Dosing Schedules of Pembrolizumab Compared to Ipilimumab in Participants with Advanced Melanoma; Q = every; W = weeks.
Robert C et al. N Engl J Med. 2015;372: For educational purposes only.

34. CheckMate 067: OS with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Wolchok et al. N Engl J Med. 2017;377: For educational purposes only.

35. Current Standard of Care of Advanced Melanoma
BRAF wild-type patients:
Single-agent nivolumab or pembrolizumab
BRAF V600 mutation-positive patients:
Targeted therapy with BRAF and MEK inhibitors

36. CheckMate 069: PFS in Patients with BRAF Mutation-positive Tumors
Nivolumab + Ipilimumab
Ipilimumab N
mPFS (Months)
(95% CI)
mPFS (Months)
BRAF Status
Mutant 32
8.61
(2.79–NR)
2.73
(0.99–5.42)
Wild-type
110 NR
(7.23–NR)
4.44
(2.76–5.32)
Nivolumab/ipilimumab combination was superior to ipilimumab monotherapy in BRAF wild-type patients
BRAF = B-Raf proto-oncogene; CheckMate 069 = Study of Nivolumab Plus Ipilimumab Compared with Ipilimumab Alone in the Treatment of Previously Untreated, Unresectable, or Metastatic Melanoma.
Hodi et al. Lancet Oncol. 2016;17:

37. CheckMate 067: OS Among Patients with or without BRAF Mutations
Patients with BRAF Mutations
Combination of ipilimumab plus nivolumab superior to ipilimumab monotherapy at 36 months regardless of BRAF status.
Patients without BRAF Mutations
CheckMate 067 = Phase III Study of Nivolumab or Nivolumab Plus Ipilimumab vs Ipilimumab Alone in Previously Untreated Advanced Melanoma.
Wolchok et al. N Engl J Med. 2017;377: For educational purposes only.

38. Current Standard of Care of Advanced Melanoma
BRAF wild-type patients:
Single-agent nivolumab or pembrolizumab
BRAF V600 mutation-positive patients:
Targeted therapy with BRAF and MEK inhibitors
Whether nivolumab/ipilimumab provides an advantage over nivolumab monotherapy remains an ongoing debate

39. Immunotherapy in Ovarian Cancer

40. JAVELIN Ovarian 200 Trial
Avelumab monotherapy vs avelumab + PLD vs PLD monotherapy in patients with platinum-resistant, recurrent ovarian cancer
ORR:
Avelumab + PLD: 13.3%
Avelumab monotherapy: 3.7%
PLD monotherapy: 4.2%
Potential clinical activity of avelumab chemotherapy to be analyzed further
JAVELIN Ovarian 200 = A Study of Avelumab Alone or in Combination with Pegylated Liposomal Doxorubicin vs PLD Alone in Patients with Platinum Resistant/Refractory Ovarian Cancer; PLD = pegylated liposomal doxorubicin.
Merck KGaA, Darmstadt, Germany, and Pfizer provide update on avelumab in platinum-resistant/refractory ovarian cancer [press release]. Darmstadt, Germany: Merck & Co Inc; November 19, 2018.

41. JAVELIN Ovarian 100 Trial
Phase III: Avelumab in combination with and/or following platinum-based chemotherapy in patients with previously untreated advanced ovarian cancer
Study discontinued as of December 21, 2018
Interim analysis indicates neither avelumab arm would demonstrate PFS advantage over chemotherapy only control.
JAVELIN Ovarian PARP 100 study and earlier phase studies are still ongoing.
Recent results from the JAVELIN Solid Tumor trial indicate antitumor efficacy and acceptable safety profile of avelumab monotherapy in refractory ovarian cancer.
JAVELIN OVARIAN 100 = Avelumab in Previously Untreated Patients with Epithelial Ovarian Cancer; JAVELIN OVARIAN PARP 100 = Avelumab and Talazoparib in Untreated Advanced Ovarian Cancer.
Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on JAVELIN Ovarian 100 Trial of avelumab in previously untreated advanced ovarian cancer [press release]. Merck/Pfizer Inc: Darmstadt, Germany/New York; December 21, 2018.
Disis et al. JAMA Oncol. 2019; doi: /jamaoncol

42. TOPACIO/KEYNOTE-162
Phase I/II: Niraparib plus pembrolizumab in recurrent platinum-resistant ovarian cancer or triple-negative breast cancer
Combination efficacy:
ORR: 25% (24% in platinum refractory disease)
Disease control rate: 68%
ORR independent on biomarker status:
26% in patients without tumor BRCA mutation
29% in patients with HRD-negative tumors
Combination safety:
Well-tolerated; incidence of grade 3/4 thrombocytopenia: 9%
HRD = homologous recombination deficiency; KEYNOTE-162/TOPACIO = Niraparib in Combination with Pembrolizumab in Patients with Triple-negative Breast Cancer or Ovarian Cancer.
Data from TOPACIO trial reported at SGO demonstrates compelling clinical activity of ZEJULA in combination with an anti-PD-1 antibody in patients with platinum resistant/refractory ovarian cancer [press release]. New Orleans, LA: Tesaro Inc; March 26, 2018.

43. irAEs

44. irAEs in Bladder Cancer

45. Incidence of AEs in Studies with Anti-PD-1/PD-L1 Antibodies
Occur in up to 2/3 patients1
25% to 40% of patients experience mild toxicities
Fatigue, flu-like symptoms, rash, pruritus
15% to 20% of patients experience moderate-to-severe toxicities
Pneumonitis, colitis diarrhea
Irreversible endocrinopathy, hypophysitis, adrenal insufficiency, immune-related diabetes occur in <1% of patients
Can occur up to 6 months into therapy2-3
Early patient reporting is key
1. Stucci S. Oncol Lett. 2017;14:5671–5680; 2. Topalian SL. J Clin Oncol. 2014;32: ; 3. Weber JS. Cancer. 2013;119:

46. National Guidelines for Management of irAEs
American Society of Clinical Oncology (ASCO):
National Comprehensive Cancer Network (NCCN):
European Society for Medical Oncology (ESMO):
Society for Immunotherapy of Cancer (SITC) [Guidelines in Progress]:

47. irAEs in Lung Cancer

48. Differentiating Immunotherapy-Induced Pneumonitis from Baseline Symptoms
No single diagnostic test
May masquerade as consolidative pneumonia, but typically will not respond to antibiotics
Patients should be aware of their baseline symptoms and report new symptoms as early as possible

49. irAEs in Renal Cancer

50. Considerations for Detecting irAEs in RCC Patients
The most common organ systems involved with nivolumab/ipilimumab combination are skin, endocrine, GI tract, liver, lung, and kidney
Hepatotoxicity detectable by blood test surveillance
Lung and colon toxicities can be more subtle, but should be recognized and managed as early as possible

51. Detecting and Managing GI irAEs in RCC Patients
TKI-induced diarrhea will typically resolve within 1–2 days, whereas immunotherapy-induced diarrhea will persist.
Clostridium difficile infection should be ruled out.
Colonoscopy/sigmoidoscopy can detect patchy erythema, biopsy will show lymphocytic infiltrate.
Grade 2–3 immunotherapy-induced diarrhea is serious and should be managed with steroids as soon as possible.
Adjunct therapy (eg, infliximab, mesalamine) can shorten the duration of corticosteroid use.
TKI = tyrosine kinase inhibitors.

52. Detecting and Managing Lung irAEs in RCC Patients
Chest X-ray alone is typically unreliable for detecting pneumonitis.
Oxygen saturation at rest can also be deceiving.
Desaturation following 6-minute walk and infiltrates detectable by CT, however minor, indicate pneumonitis.
CT = computed tomography.

53. Special Considerations for irAE Management with Corticosteroids

54. Can Steroid Administration Blunt the Effects of the Immunotherapy?
No definitive answer at this point in time.
For toxicities that might rapidly progress to become life-threatening, such as colitis and pneumonitis, a conservative approach is recommended.
Current evidence suggests that short-term immune suppression does not impact therapeutic benefit from immunotherapy.1-2
1. Webber J et al. J Clin Oncol. 2017;35: ; 2. Schadendorf D et al. J Clin Oncol. 2017;35:

55. Can Steroid Administration Blunt the Effects of the Immunotherapy?
No definitive answer at this point in time.
For toxicities that might rapidly progress to become life-threatening, such as colitis and pneumonitis, a conservative approach is recommended.
Current evidence suggests that short-term immune suppression does not impact therapeutic benefit from immunotherapy.1-2
For colitis, CT scan or colonoscopy with biopsies can detect acute and chronic inflammatory changes.
1. Webber J et al. J Clin Oncol. 2017;35: ; 2. Schadendorf D et al. J Clin Oncol. 2017;35:

56. Future Directions

57. RCC Emerging immunotherapy/anti-VEGF combinations:
Avelumab + axitinib
Pembrolizumab + axitinib
Atezolizumab + bevacizumab
Considerations for regimen selection
CR rate and OS
Time to CR and survival advantage
Patient selection biomarkers
Role of PD-L1?

58. RCC Emerging immunotherapy/anti-VEGF combinations:
Avelumab + axitinib
Pembrolizumab + axitinib
Atezolizumab + bevacizumab
Considerations for regimen selection
CR rate and OS
Time to CR and survival advantage
Patient selection biomarkers
Role of PD-L1?

59. Lung Cancer
Mechanisms of primary and acquired resistance

60. Lung Cancer Mechanisms of primary and acquired resistance
Response biomarkers beyond PD-L1
Tumor mutational burden

61. Bladder Cancer Role of PD-L1 status in patient selection
Immunotherapy + chemotherapy combinations
Impact of immunotherapy in the localized disease setting

62. Bladder Cancer Role of PD-L1 status in patient selection
Immunotherapy + chemotherapy combinations
Impact of immunotherapy in the localized disease setting
Efficacy of immunotherapy in non-muscle invasive bladder cancer

63. KEYNOTE-057: Pembrolizumab in Patients with BCG-Refractory, High-Risk Nonmuscle Invasive Bladder Cancer
Interim analysis demonstrated a CR rate of 38.8% (n = 103) at 3 months with pembrolizumab in patients whose disease was unresponsive to BCG therapy and who were ineligible for radical cystectomy.
BCG = Bacillus Calmette-Guérin; KEYNOTE-057 = Study of Pembrolizumab in Participants with High Risk Nonmuscle Invasive Bladder Cancer.
de Wit R et al. Pembrolizumab for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG): phase II KEYNOTE-057 trial. Presented at: European Society of Medical Oncology 2018 Congress; October 19-23: Munich, Germany. Abstract 864O.