DURVALUMAB IN STAGE III NSCLC CASE PRESENTATION

• A 65 year old male presented with abdominal pain in March 2015

• PMH: Hypertension

• Social History: 1 pack daily since the age of 18. Alcohol use. • CT scan of the abdomen showed a suspicious mass in the right middle lung

• CT of the chest on 6/1/15 showed a partially cavitary mass in the right mid lung and hilar and mediastinal adenopathy

• Bronchoscopy on 6/30/15 ‐FNA of 4R and 11R showed squamous cell carcinoma IMAGING on 7/15/15 • Stage IIIC (T2aN3M0) squamous cell carcinoma of the right lung

• Started on concurrent radiation and Cisplatin and Etoposide

• Completed on 9/21/15 CT Chest on 9/30/15 • Patient enrolled in the PACIFIC study on 11/2/15 ‐> IV Durvalumab 10 mg/kg vs Placebo every 2 weeks for one year

• Treatment completed on 10/17/16 CT Chest on 2/24/16 CT Chest on 1/28/19 TSH Free T4

11/16/15 0.071 3.18

12/14/15 0.029 2.7

1/4/16 0.5 0.51

1/11/16 20.447 0.3

2/8/16 99 <0.25 Levothyroxine started

2/22/16 36.396 0.56

3/7/16 2.511 1.05

• Levothyroxine 137 mcg once daily. Most recent thyroid labs normal

• Type 2 diabetes mellitus in early 2018. On metformin and glipizide. LUNG CANCER

• Approximately 234,000 patients annually • Frequency decreasing • Leading cause of cancer‐related mortality in the United States and worldwide • Over 154,000 deaths annually • Deaths declining in both men and women

Siegel RL, et.al. CA Cancer J Clin.2018. TYPES OF LUNG CANCER STAGE III LUNG CANCER

• 1/3 of patients

• T4 ‐ T3 N1 ‐ N2 – N3

• Unresectable (superior sulcus (Pancoast) tumor, most T4 lesions, N2 disease, N3 disease)

• Concurrent chemoradiation

• Cisplatin and Etoposide

• Weekly Carboplatin Taxol

• Cisplatin and Alimta (Nonsquamous cell lung cancer)

Belani CP, et.al. J Clin Oncol. 2005. • Median PFS after chemoradiation 8 months

• 15% survival at 5 years

Auperin A, et.al. J Clin Oncol. 2010. NSCLC 5‐year OS PROGRAMMED CELL DEATH‐1 (PD‐1) and PDL‐1 CHECKPOINT INHIBITORS

• PD‐1 inhibitors ‐Pembrolizumab (Keytruda) ‐Nivolumab (Opdivo) ‐Cemiplimab (Libtayo)

• PDL‐1 inhibitors ‐Atezolizumab (Tecentriq) ‐Durvalumab (Imfinzi) ‐Avelumab (Bavencio) PACIFIC TRIAL

Durvalumab after Chemoradiotherapy in Stage III Non–Small‐Cell Lung Cancer

Scott J. Antonia, et.al. N Engl J Med 2017; 377:1919‐1929 • Durvalumab had encouraging antitumor activity in early‐phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC

• Approved for patients with locally advanced or metastatic urothelial carcinoma who had received platinum‐based chemotherapy

• Preclinical evidence suggesting that chemotherapy and radiotherapy may up‐regulate PD‐L1 expression in tumor cells

Zhang P, et.al. Mol Immunol. 2008.

Progression Free survival

• 16.8 months vs 5.6 months

• 12‐month PFS rate 55.9% vs 35.3%

• 18‐month PFS rate 44.2% vs 27.0%

• ORR 28.4% vs. 16.0%

• Longer duration of response. • 24‐month overall survival rate 66.3% vs 55.6%

POSSIBLE SIDE EFFECTS Adverse events: 96.8% vs 94.9%

Grade 3 or 4 adverse events: 29.9% vs 26.1%

Pneumonia: 4.4% vs 3.8% IMMUNOTHERAPY IN NSCLC

• Stage IV disease. First line treatment.

• Pembrolizumab vs Platinum based therapy (Keynote‐024) ‐PDL‐1: 50% or more ‐Follow up 11.2 months, PFS 10.3 vs 6 months ‐Further follow up, OS 30 vs 14.2 months

• Carboplatin, Pemetrexed with Pembrolizumab or Placebo (Keynote‐189) ‐PFS 8.8 vs 4.9 months ‐12 month OS 69.2% vs 49%.

• Carboplatin, Taxol, and Avastin with Atezolizumab or Placebo (IMpower150) ‐PFS 8.3 vs 6.8 months ‐OS 19.2 versus 14.7 months

Reck M, et.al. N Engl J Med. 2016. Socinski MA, et.al. N Engl J Med. 2018. IMMUNOTHERAPY IN NSCLC

• Carboplatin, Taxol/Abraxane with either Pembrolizumab or placebo (Keynote‐407) ‐OS 15.9 vs 11.3 months ‐PSF 6.4 vs 4.8 months

Paz‐AresL, et.al. N Engl J Med.2018. IMMUNOTHERAPY IN NSCLC

• Recurrent disease

• Nivolumab versus Docetaxel (Checkmate trial)

• Nonsquamous histology ‐OS 12.2 versus 9.4 months ‐ORR 19 versus 12% ‐Duration of response 18 versus 6 months

• Squamous histology • Nivolumab versus Docetaxel • OS 9.2 vs 6.0 months • ORR 20 vs 9% • Duration of response 25 versus 8 months

Brahmer J, et.al. N Engl J Med. 2015. Horn, et.al. J Clin Oncol.2015. IMMUNOTHERAPY IN NSCLC

• Pembrolizumab vs Docetaxel (Keynote‐010) ‐OS 10.4 and 12.7 months for Pembrolizumab low and high dose vs 8.5 months ‐Median PFS similar (4 months) ‐Better tolerated

• Atezolizumab versus Docetaxel ‐OS 13.8 versus 9.6 months ‐Duration of response 16.3 vs 6.2 months ‐PFS 2.8 vs 4 months ‐ORR 14 vs 13 percent

Herbst RS, Baas P, et.al. Lancet. 2016. Rittmeyer A, et.al. Lancet. 2017. • Durvalumab is standard maintenance treatment in stage III NSCLC

• Immunotherapy plays major role in stage IV NSCLC in the first line setting and also in recurrence THANK YOU