Squamous Cell NSCLC: Differentiating Between Progression and Pseudoprogression

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2 Squamous Cell NSCLC: Differentiating Between Progression and Pseudoprogression David R. Spigel, M.D. Program Director, Lung Cancer Research Sarah Cannon Research Institute Nashville, TN

3 Case of NR: Initial Presentation 56 yo woman w/ L-shoulder/back pain x 2 mos Smoked 1 PPD x 26 yrs, quit 6 yrs ago CXR- LUL mass, confirmed by CT PET/CT- LUL mass w/direct invasion of 2 nd rib, mildly enlarged mediastinal LNs, and T5 transverse process Brain MRI- negative CT-guided biopsy: poorly diff squamous NSCLC 3

4 NR: First-Line Therapy Starts cisplatin/gemcitabine + denosumab SD on first scans; fatigue, nausea/vomiting Switched to carboplatin/gemcitabine Repeat CT shows PD; increased pain Seeks opinion in Japan - several months off therapy PD and increased pain 4

5 Nivolumab: Phase I (N=129) Gettinger SN. JCO doi: /jco

6 Nivolumab: 063 Phase II Squamous Rizvi NA, Lancet Onc

7 Nivolumab: 017 Phase III Squamous Nivolumab URL Accessed May 19,2015: 7

8 NR: Immunotherapy Enrolls in a trial of nivolumab 1/2013 Her pain decreases over weeks Scan shows a PR Eventually off opioids at 16 weeks However, new R axillary LAN on CT, along with fever (102 F), lymphopeniact. 8

9 Question 1: How Do You Proceed? 1) Discontinue nivolumab due to PD 2) Discontinue nivolumab due to toxicity 3) Continue nivolumab and initiate antibiotics 4) Continue nivolumab and initiate steroids 5) Biopsy the axillary nodes 9

10 NR: Immunotherapy You continue nivolumab Subsequent scan shows further enlargement of axillary LAN, along with shrinkage of mediastinal LAN and LUL lesion She develops fever to 103F with weakness & hypotension (BP 86/40) Admitted and started on broad spectrum antibiotics 10

11 Question 2: Do You Initiate Steroids? 1) Yes 2) No 11

12 Question 3: How Do You Proceed? 1) Permanently discontinue nivolumab due to PD 2) Permanently discontinue nivolumab due to toxicity 3) Hold nivolumab, consider restarting if she improves 4) Continue nivolumab with supportive measures 12

13 Question 4: Do You Seek Additional Tissue? 1) No 2) Yes, from a mediastinal node 3) Yes, from an axillary node 4) Yes, from the primary left lung tumor 13

14 NR: A Tissue Diagnosis Stabilizes on steroids; undergoes biopsy of axillary node Path: no cancer; necrotizing adenopathy (Kikuchi synd) After discussion with sponsor, COX-2 inhibitor started with dexamethasone 8 mg PO BID Dexamethasone is tapered off at 4 weeks; celecoxib continued Follow-up scan shows stable findings in chest 14

15 Nivolumab: Phase I (N=129) Gettinger SN. JCO doi: /jco

16 Phase 1 Dose Expansion Study with MEDI4736: Efficacy Segal NH, ASCO Abstract

17 Different Response Patterns in Melanoma: Ipilimumab Slide 9 CCR

18 Question 5: Do You Resume Immunotherapy? 1) Yes 2) No 18

19 NR: Ongoing response Resumes nivolumab (along with celecoxib) and demonstrates further improvement on subsequent scans Remains on nivolumab over 32 months since diagnosis - no pain and no limitation in activities 19

20 Pembrolizumab: KEYNOTE-001 PFS and OS Garon EB, NEJM

21 Merck Press Release October 27, 2014 Merck Receives FDA Breakthrough Therapy Designation for pembrolizumab in Advanced Non-Small Cell Lung Cancer WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to pembrolizumab, the company s anti-pd-1 therapy, for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. This is the second Breakthrough Therapy Designation granted for pembrolizumab. 21

22 MPDL3280A Herbst R. Nature

23 Genentech Press Release Feb 1, 2015 FDA Grants Breakthrough Therapy Designation for Genentech s Investigational Cancer Immunotherapy MPDL3280A (anti-pdl1) in Non-Small Cell Lung Cancer Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that it has received a second Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for its investigational cancer immunotherapy MPDL3280A (anti-pdl1). The designation was granted for the treatment of people with PD-L1 (Programmed Death-Ligand 1) positive non-small cell lung cancer (NSCLC) whose disease has progressed during or after platinum-based chemotherapy (and an appropriate targeted therapy for those with an EGFR mutation-positive or ALK-positive tumor). 23

24 MPDL3280A: POPLAR Randomized Phase II Media Release Basel, 14 May, 2015 MPDL3280A doubled the likelihood of survival compared with chemotherapy Results indicated PD-L1 expression correlated with MPDL3280A efficacy Global, randomised Phase II study in previously treated NSCLC MPDL3280A (anti-pdl1) doubled the likelihood of survival (overall survival [OS]; HR=0.47) in people whose cancer expressed the highest levels of PD-L1 (programmed death ligand-1) compared with docetaxel An improvement in survival was also observed in people who had medium and high (HR=0.56) or any level of PD-L1 expression (HR=0.63) MPDL3280A was generally well tolerated and adverse events were consistent with what has been previously reported 24

25 MEDI Segal NH, ASCO Abstract 3002

26 SWOG - LUNG MASTER PROTOCOL Phase II/III - S1400 Advanced stage refractory SCCA patients Screening registration Common Broad Platform CLIA Biomarker Profiling* Specific markers for screening: P13K PI3KCA mutation CDK4/6 CCND1, Cdk6 amplification, CDKN2 deletion and mutation FGFR FGFR amplification, mutation, fusion HGF c-met expression Match (known positive biomarker) Sub-study Assessment** Non-match (unknown negative biomarker) Non-match Sub-study A Anti-PD-L1 CT MEDI4736 Biomarker-driven AZ/MedImmune Sub-study B Target P13K Sub-study C Target CDK4/6 Sub-study D Target FGFR Sub-study E Target HGF GDC-0032 CT Palbociclib CT AZD CT CT Rilotumumab + E E Genentech Pfizer AZ Amgen Endpoint (interim PFS) OS Endpoint (interim PFS) OS Endpoint (interim PFS) OS Endpoint (interim PFS) OS 26

27 Thank You 27

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