1. The Use of New Biologics in the Treatment of Cancer
Amanda Y. Laubenthal, DO
Hematologist/Oncologist

2. Overview Where have we been and how did we get here? What has changed?
Known examples
General principles of immunotherapy
What has changed?
New agents
New indications
Special considerations
Adverse effects
Response patterns
Cost

3. Which of the following is true?
1) All immunotherapy is biologic therapy.
2) All biologic therapy is immunotherapy.
Choice 1

4. What does “BIOLOGIC” mean in the treatment of cancer?
Preparations created from living organisms by biological processes
Vaccines
HPV vaccine
Hepatitis B vaccine
Medications
Growth factors—G-CSF, ESA
Cytokines--IL-2, IFN-α
Monoclonal antibodies—rituximab, trastuzumab
Newer checkpoint inhibitors
Oncolytic virus therapy
T cell therapy

5. Question
What was the first monoclonal antibody approved in the treatment of cancer?
Rituximab, 1997

7. Immunotherapy I Might Make U Nod Off. Try Hard Earn Rewarding
Academic
Pearls.
Yes?
We are going to talk about the basics of immunotherapy.
I don’t know about you, but blood and immunology was NOT my favorite block in med school.

8. Basics of immunotherapy
Type of cancer treatment that uses our own immune system to fight cancer while hopefully sparing normal cells/tissues
Immunotherapy ≠ biologic therapy
Cancer does its best to “escape” the immune system

9. Immune System ATTACK

10. Control of tumor by immune system

11. Anti-CTLA4 and PD1

12. Antibody Therapy

13. Vaccine therapy
-prostate cancer

14. CTLA4 inhibitors “release the brake”

15. indications—ipilimumab (yervoy)--Anti CTLA-4
Melanoma:
Unresectable or metastatic
Adjuvant treatment

16. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Kaplan–Meier Curves for OS and PFS
N = 1,861
Median OS was 11.4 months (95% CI, 10.7 to 12.1 mnths)
3-year survival rate of 22% (95%CI, 20% to 24%)
The median follow-up for overall survival (Panel A) in the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group was 21.0 months, and the median overall survival was 10.0 months (95% CI, 8.5 to 11.5); in the ipilimumab-alone group, the median follow-up was 27.8 months, and the median overall survival, 10.1 months (95% CI, 8.0 to 13.8); and in the gp100-alone group, the median follow-up was 17.2 months, and the median overall survival, 6.4 months (95% CI, 5.5 to 8.7). The median progression-free survival (Panel B) was 2.76 months (95% CI, 2.73 to 2.79) in the ipilimumab-plus-gp100 group, 2.86 months (95% CI, 2.76 to 3.02) in the ipilimumab-alone group, and 2.76 months (95% CI, 2.73 to 2.83) in the gp100-alone group. The rates of progression-free survival at week 12 were 49.1% (95% CI, 44.1 to 53.9) in the ipilimumab-plus-gp100 group, 57.7% (95% CI, 48.9 to 65.5) in the ipilimumab-alone group, and 48.5% (95% CI, 39.6 to 56.7) in the gp100-alone group.
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
NEJM 363(8): , 2010
Hodi FS et al. N Engl J Med 2010;363:
Pooled Analysis of Long-Term Survival Data From Phase II
and Phase III Trials (10 pros and 2 retro) of Ipilimumab in Unresectable or Metastatic Melanoma. Schadendorf et al JCO 2015

17. PD-1 inhibitors

18. Question
In metastatic/locally-advanced, unresectable non- small cell lung carcinoma, which tests should be performed to direct treatment?
This requires tissue!
EGFR (category 1)
ALK (category 1)
ROS-1
PDL-1

19. Indications—pembrolizumab (keytruda)—pd-1 inhibitor
Recurrent or metastatic squamous cell H&N cancer
Metastatic melanoma
Metastatic NSCLC
First-line
High PD-L1 expression [tumor proportion score (TPS) ≥50%]
Second-line or after
For tumors that express PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing chemotherapy
Off-label use in merkel cell

20. Indications—Nivolumab (opdivo)—PD-1 inhibitor
Renal cell carcinoma
Metastatic melanoma
Metastatic NSCLC
Similar efficacy in non-PDL1 expressing tumors
Hodgkin lymphoma - relapsed or progressed after auto transplant
Recurrent or metastatic squamous cell H&N cancer
Off-label use in SCLC

21. Estimated 12-month survival rates
6-month PFS - P<0.001
47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab
The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab
every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab
(hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens
versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to
0.72, respectively).
Estimated 12-month survival rates were 74.1%, 68.4%, and
58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63;
95% CI, 0.47 to 0.83; P = ; hazard ratio for pembrolizumab every 3 weeks,
0.69; 95% CI, 0.52 to 0.90; P = ).
Estimated 12-month survival rates
74.1% for pembrolizumab every 2 weeks, 68.4% for pembrolizumab every 3 weeks
58.2% for ipilimumab
Robert C et al. N Engl J Med 2015;372:

22. 11.5 months with nivolumab plus ipilimumab 6.9 months with nivolumab
mPFS
11.5 months with nivolumab plus ipilimumab
6.9 months with nivolumab
2.9 months with ipilimumab
P<0.001
In patients with tumors positive for the PD-1 ligand (PD-L1), the median
progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab
group and in the nivolumab group, but in patients with PD-L1–negative tumors,
progression-free survival was longer with the combination therapy than with
nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI,
2.8 to 7.1]).
PFS
11.2 months in combination therapy than with
5.3 in nivolumab alone
PFS
14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group

23. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer

24. Checkmate 057: Kaplan-Meier Plots of Progression-free Survival at the 1%, 5% and 10% PD-L1 Expression Levels.
Phase III Nivolumab trial

25. Indications—atezolizumab (tecentriq)—pdl1 inhibitor
Advanced or metastatic urothelial carcinoma
Metastatic NSCLC

26. Atezolizumab: Refractory Urothelial Cancer
Rosenberg et al Lancet 2016

27. What’s the downside? Name an organ Add an –itis

28. Weber JS et al, Clin Oncol 2012
Timeline of effects
Weber JS et al, Clin Oncol 2012

30. Ipilimumab colitis on colonoscopy Ipilimumab skin toxicity
World J Gastroenterol. Apr 14, 2015; 21(14): ,

31. Primary care consideration
Is it okay to start steroids on a patient receiving immunotherapy?
That depends on why you are doing it
Please check with the oncologist
Steroids will potentially decrease efficacy
If toxicity, steroids need to be started, but should be done under care of oncologist

32. Management of adverse effects
Hold treatment
STEROIDS!!!
Severe/Grade 3: 1-2 mg/kg prednisone dosing with slow taper over one month
Mild-moderate/Grade 2: 0.5mg/kg prednisone
Rituximab for diarrhea unresponsive to steroids
Mycophenolate mofetil for severe hepatitis
Pneumocystis prophylaxis if receiving ≥20mg prednisone daily for four weeks
Diarrea unresponsive at 1 week
Can give concurrently for hepatitis if severe
NCCN guideline on pneumocystis

33. Primary care/emergency medicine consideration
Your patient with metastatic lung cancer goes to the ER for acute shortness of breath. A CT with PE protocol is performed. The liver lesions appear larger than the last CT scan done at baseline 6 weeks prior. The patient is on nivolumab. You go in to speak with the patient and tell her that:
1) Her cancer appears to be progressive.
2) Lesions are larger, but that does not mean her cancer is worse.

34. pseudoprogression
Metastatic lung cancer, monitored by CEA

35. response I took out the WHO guidelines

36. CAR-T therapy http://www.slideshare.net/spa718/4-keiya-ozawa
Cytokine release
Neurotoxicity
CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains

37. CAR-T therapy Most progress and data in B-cell lymphomas and leukemias
Particularly ALL
Looking at solid tumors
Adverse effects
On-target, off-tumor activity (ex. Her2)
Cytokine release—fever, hypotension, hypoxia
Neurotoxicity—delirium, dysphasia, akinetic mutism, seizures
Her-2 expressed at low levels in heart and lungs

38. Question
What virus are researchers using to treat refractory glioblastoma multiforme?
This is NOT yet approved, despite the excitement generated by “60 Minutes”
Poliovirus. In the studies, they are making sure that patients are getting a polio booster at least 2 weeks prior to treatment

39. Oncolytic virus therapy
Talimogene laherparepvec, or T-VEC (Imlygic)
Genetically modified herpes virus
Injected directly into metastatic melanoma—cutaneous, subcutaneous, and nodal
First oncolytic therapy approved in 2015
Did not change OS
Recombinant oncolytic poliovirus
Granted breakthrough status by FDA in 2015 for glioblastoma multiforme
Phase I trials reported increased OS
Your physician injects T-VEC directly into melanoma tumors. The virus then replicates within the cells, causing them to rupture and die. T-VEC is a local treatment, which means that it is applied directly to melanoma lesions to treat those cells.
The exact way that T-VEC works in the immune system is not fully known. Cancer experts believe that, in addition to directly killing cells, the virus may also produce an immune response against melanoma by releasing:
Antigens (substances that promote an immune response) shed from the tumor cells
A protein (GM-CSF) that stimulates the immune system

40. Cost Ipilimumab Nivolumab Pembrolizumab Atezolizumab Imlygic
$30,000/dose
$120,000 per standard treatment regimen for metastatic disease.
Nivolumab
$12,400/month
Pembrolizumab
$12,500/month
Atezolizumab
Imlygic
$65,000, on average, per patient

41. EXCELLENT RESOURCE
impact/timeline-of-progress/timeline-detail
If you want a comprehensive timeline

42. Where are we headed?
Chemotherapy + immunotherapy in solid tumors—pancreas, colon
Oncolytic virus therapy in more solid tumors
CAR-T therapy in solid tumors
The moon?
Opdivo +chemo in colon and pancrease
Keytruda + Herceptin in breast, gastric

43. references Journal of Clinical Oncology NCCN website Cancer.org
Utdol.com
Cancernetwork.com
Fda.gov
Keytruda.com
Opdivohcp.com
Antigen-Receptors-Modified-T-Cells-for#
US:IE-Address&ie=&oe=
treatment-for-brain-cancer
progress/timeline-detail
guide.pdf
Many thanks to Zohra Noorudin, MD for the study figures used in the presentation.