Concept to Practice: New Advances in the Treatment of GI Cancers

Transcription

1 Concept to Practice: New Advances in the Treatment of GI Cancers 2016 Community Oncology Alliance Conference Orlando, FL Thomas George, MD, FACP Director, GI Oncology Program Director, Experimental Therapeutics Incubator University of Florida Health Cancer

2 Disclosures Institutional Research Funding: Bayer Bristol Myers Squibb Celgene NewLink Genetics Consultant: Bayer NewLink Genetics

3 Educational Objectives 1. Review the past year of research leading to new treatments for patients with GI cancers 2. Discuss the incorporation of these treatments in the context of current standards of care 3. Anticipate upcoming trial results which may further change the treatment landscape

4 2016 Estimated US Cancer: Prostate 21% Lung & bronchus 14% Colorectal 8% Urinary bladder 7% Melanoma 6% NHL 5% Kidney 5% Leukemia 4% H&N 4% Liver/Cholangio 3% All Other Sites 23% New GI Cases Men Women 29% Breast 13% Lung & bronchus 8% Colorectal 7% Uterine corpus 6% Thyroid 4% NHL 3% Melanoma 3% Leukemia 3% Pancreas 3% Kidney 21% All Other Sites ACS Surveillance Research 2015

5 2016 Estimated US Cancer: Lung & bronchus 27% Prostate 8% Colorectal 8% Pancreas 7% Liver/Cholangio 6% Leukemia 4% Esophagus 4% Urinary bladder 4% NHL 4% Brain/CNS 3% All other sites 25% GI Cancer Deaths Men Women 26% Lung & bronchus 14% Breast 8% Colorectal 7% Pancreas 5% Ovary 4% Uterine corpus 4% Leukemia 3% Liver/Cholangio 3% NHL 2% Brain/CNS 24% All other sites ACS Surveillance Research 2015

6 Taken All Together Colorectal cancer is 3 rd most common cancer and the 2 nd leading cause of cancer deaths Slowly declining rates of incidence and deaths Pancreatic cancer is the 3 rd leading cause of cancer deaths Rising rates à projected as 2 nd leading cause of cancer deaths by 2030 Liver and cholangio rates are rising worldwide Rahib L et al. Cancer Res Jun 1;74(11):

7 Esophagogastric Adenocarcinoma & Anti-VEGF therapy Bevacizumab FAILED to demonstrate OS advantage in 1 st -line therapy (AVAGAST Trial) Anti-VEGF therapy demonstrated activity and led to FDAapproval of Ramucirumab alone or in combination with paclitaxel in previously treated mega REGARD & RAINBOW trials Taxanes are the most widely used 2 nd -line tx for mega Ohtsu A, et al. J Clin Oncol. 2011;29:

8 REGARD Trial BSC ± Ramucirumab 2 nd Line Treatment Pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidinecontaining combination therapy, ECOG PS 0-1 (N = 355) BSC + Ramucirumab 8 mg/kg IV q2w (n = 238) BSC + Placebo (n = 117) Treatment until PD, unacceptable toxicity, or death Primary objective: OS Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety Fuchs CS, et al. Lancet. 2014;383:31-39

9 RAINBOW Trial Paclitaxel ± Ramucirumab 2 nd Line Treatment Pts with metastatic or locally adv unresectable gastric or GEJ cancer progressing on first-line platinum and fluoropyrimidine- +/- anthracycline containing combination therapy, ECOG PS 0-1 (N = 665) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Ramucirumab 8 mg/kg Days 1, 15 (n = 330) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Placebo Days 1, 15 (n = 335) Treat until PD or intolerable toxicity Primary endpoint: OS Secondary endpoints: PFS, ORR, TTP Wilke H, et al. Lancet Oncol. 2014;15:

10 BSC +/- Ram Paclitaxel +/- Ram BSC BSC + Ram Paclitaxel Paclitaxel + Ram Median OS (mo) HR: (95% CI: ; P=.0473) HR: (95% CI: ; P =.0169) Median PFS (mo) ORR (%) Casak SJ, et al. Clin Cancer Res 2015;21:

11 RAINFALL Trial Capecitabine/5-FU + Cisplatin ± Ramucirumab First line mega ClinicalTrials.gov. NCT

12 What about Immunotherapy?

13 KEYNOTE-012: Gastric Cancer Cohort Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001)

14 Maximum Percentage Change From Baseline in Tumor Sizea (RECIST v1.1, Central Review) Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001)

15 Not Quite Ready for Prime Time Pembrolizumab - pib (restricted to PD-L1 overexpressing) Toxicity Nothing new 22% ORR Median duration of response = 10mo Median OS = 11mo Avelumab - unselected 2 nd line mega 15% ORR; 50% disease control rate; mpfs = ~4mo Ongoing studies (phase I, II and III) w/ single and double checkpoint inhibitors in EGA Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001) Chung HC et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 167)

16 Gastroesophageal Update Summary New approval for Ramucirumab alone or in combination with paclitaxel in second-line mega Immunomodulators look promising, but not home run More studies are ongoing Don t forget to confirm HER2 status of patient s tumor Trastuzumab in combination with chemotherapy

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18 Systemic Therapy Options (PDAC) Study Treatment Control Patients (n=total) Median OS (mo) 1-year OS (%) p-value (median OS) Burris III HA Gem 5FU vs vs NCI Canada Gem+erlotinib Gem vs vs Von Hoff DD Gem+ nab-paclitaxel Gem vs vs 22 <0.001 PRODIGE Intergroup FOLFIRINOX Gem vs vs 20 < years of Progress Burris HA, et al. J Clin Oncol. 1997;15: Moore MJ, et al. J Clin Oncol. 2007;25: Von Hoff DD, et al. N Engl J Med. 2013;369: Conroy T, et al. N Engl J Med. 2011;364:

19 Systemic Therapy Options (PDAC) Study Treatment Control Patients (n=total) Median OS (mo) 1-year OS (%) p-value (median OS) Burris III HA Gem 5FU vs vs NCI Canada Gem+erlotinib Gem vs vs Von Hoff DD Gem+ nab-paclitaxel Gem vs vs 22 <0.001 PRODIGE Intergroup FOLFIRINOX Gem vs vs 20 < years of Progress Burris HA, et al. J Clin Oncol. 1997;15: Moore MJ, et al. J Clin Oncol. 2007;25: Von Hoff DD, et al. N Engl J Med. 2013;369: Conroy T, et al. N Engl J Med. 2011;364:

20 My Summary of Metastatic PCa Gemcitabine Gem + nab Pac FOLFIRINOX

21 My Summary of Metastatic PCa Gemcitabine Gem + nab Pac FOLFIRINOX 6mo 9mo 12mo

22 My Summary of Metastatic PCa Gemcitabine Gem + nab Pac FOLFIRINOX 6mo 9mo 12mo PS <2 PS <1 PS 0

23 My Summary of Metastatic PCa Gemcitabine + Erlotinib 6mo (unless rash ~9) PS <2 Gemcitabine Gem + nab Pac FOLFIRINOX 6mo 9mo 12mo PS <2 PS <1 PS 0

24 Then What. Most patients will only see one line of treatment For those that are fit, there are several options: Clinical trial Use what you didn t use in first line OR.. Nanoliposomal irinotecan (MM-398) w/ 5-FU/LV NCCN guidelines. v Wang-Gillam A, el al. Lancet 2016;387(10018):545-57

25 NAPOLI-1: Phase III Second-line mpca Nanoliposomal formulation increases half-life/auc preferentially increases tumor exposure to irinotecan (SN-38) Pts with metastatic pancreatic cancer who progressed on gemcitabinebased therapy, KPS 70 (N = 417) Nal-IRI 120 mg/m 2 q3w (n = 151) Nal-IRI 80 mg/m FU/LV* 2400/400 mg/m 2 q2w (n = 117) 5-FU/LV 2000/200 mg/m 2 /wk x 4 q6w (n = 119) Wang-Gillam A, el al. Lancet 2016;387(10018):545-57

26 Median OS 6.1 vs. 4.2mo Median PFS 3.1 vs. 1.5mo Wang-Gillam A, el al. Lancet 2016;387(10018):545-57

27 Wang-Gillam A, el al. Lancet 2016;387(10018):545-57

28 Adjuvant Trials On Horizon With appreciation to M. Tempero

29 Pancreatic Update Summary Still continue to struggle with development of REALLY effective systemic therapies Immunotherapies? combinations will be required 1 st AND 2 nd line systemic treatment options are now supported by data Will have data soon on the value of moving multiagent treatments to earlier stages of disease

30 Colorectal Cancer Prevention is the best treatment 80% by 2018 screening national initiative FIT testing now recommended over FOBT Don t do the following. Bouvard V, et al. Lancet Oncol Dec;16(16):

31 Colorectal Cancer An interesting potential Do 4 cups/day was associated with reduced recurrence and mortality (HR 0.48; 95% CI, 0.25 to 0.91; P=0.002) Guercio B, et al. J Clin Oncol Nov 1;33(31):

32 Colorectal Cancer Another interesting potential Do Clinical trial in mcrc measuring and treating w/ VitD as adjunct to chemo is ongoing Ng K, et al. J Clin Oncol 33, 2015 (suppl; abstr 3503)

33 Colorectal Cancer Another interesting potential Do A definite DO Clinical trial in mcrc measuring and treating w/ VitD as adjunct to chemo is ongoing Cao Y, et al., JAMA Oncol Mar 3. doi: /jamaoncol

34 Rectal Cancer in 2015 TCGA data confirm rectal and colon are same disease just differ geographically Trimodality therapy is SOC for stage II and III disease Pre-op chemort (CIVI 5FU or Capecitabine) Lap-assisted is non-inferior to open resection Systemic therapy is recommended regardless of pathology after CRT THE FOCUS of active NCI clinical trials is now modality relevancy in the context of Total Neoadjuvant Therapy NCCN guidelines Allegra CJ, et al. J Natl Cancer Inst Sep 14;107(11) Stevenson AR, et al., JAMA Oct 6;314(13):

35 Rectal Cancer in 2016 & onward Using neoadjuvant chemotherapy to test. Selective incorporation of novel chemo or radiotherapy sensitizers to drive up pcr (NRG TNT Trial ; NCT#Pending) Selective elimination of radiotherapy (ALLIANCE PROSPECT; NCT ) Selective elimination of surgery ( Watch and Wait trials; NCT ) NCCN guidelines

36 mcrc Treatment Sequencing Still awaiting updates to CALGB Venook AP, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)

37 mcrc First line therapy: Dealer s Choice Venook AP, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)

38 Definition of RAS Mutation ASCO Provisional Clinical Opinion Update 2015 Allegra CJ, et al. J Clin Oncol 2009;27: Allegra CJ, et al. J Clin Oncol Jan 10;34(2):179-85

39 Then What. Most patients will see multiple lines of palliative treatments For those that are fit, there are several options: Clinical trial Use what you didn t use in first line Regorafenib or alternative anti-vegf therapies OR.. TAS-102 NCCN guidelines. v Mayer RJ, el al. N Engl J Med May 14;372(20):

40 Oral combination of trifluridine and tipiracil Trifluridine is a fluoropyrimidine which inhibits TS Tipiracilinterferes with the deactivation of trifluridine 35mg/m 2 PO BID D1-5, D8-12 q28 days TAS-102 vs. Placebo in 800 patients Had to have previously been treated w/ FP, oxali, iri, bev +/- anti-egfr Well balanced arms Primary endpoint = OS Mayer RJ, el al. N Engl J Med May 14;372(20):

41 Mayer RJ, el al. N Engl J Med May 14;372(20):

42 Mayer RJ, el al. N Engl J Med May 14;372(20):

43 Median OS 7.1 vs 5.3mo HR 0.68; P<0.001 Median PFS 2 vs 1.7 mo HR for progression at 6mo 0.48; P<0.001 Mayer RJ, el al. N Engl J Med May 14;372(20):

44 Not Capecitabine Mayer RJ, el al. N Engl J Med May 14;372(20):

45 Mayer RJ, el al. N Engl J Med May 14;372(20):

46 How to incorporate? No head to head comparisons w/ Regorafenib Activity: Equitable Tolerability: TAS-102 > Regorafenib Two options: Use Rego first since you know benefit is tied to tolerance Use TAS-102 first since you may not get another shot Extended survival is related to seeing all active agents Sequencing studies are coming.

47 What about Immunotherapy?

48 Baseline Characteristics MMR-Deficient CRC (n = 13) MMR-Proficient CRC (n = 25) MMR-Deficient Other Tumors (n = 10) Median age, yrs Diagnosis, % CRC Ampullary/biliary Endometrial Small bowel Prostate Gastric prior therapies, % Lynch syndrome, % ORR Disease control rate Le DT, el al. N Engl J Med May 14;372(20):

49 Le DT, el al. N Engl J Med May 14;372(20):

50 Ongoing studies to confirm benefit including 1 st line Pembro vs. chemo (KEYNOTE-177; NCT ) in MSI-H or MMR-D mcrc Additional combinations with diff agents/chemo ongoing MSI testing should be performed on ALL patients w/ mcrc Identification of family syndrome in absence of + FH Biomarker for immunotherapy consideration NCCN guidelines. v2.2016

51 Summary New agents in refractory EGA, pancreatic and CRC have come into clinical practice Moving them earlier in treatment is high priority Upcoming results of perioperative trials in pancreatic and rectal cancers could be clinical practice game changers Immunotherapy is gaining relevancy in GI cancers Personalized treatment decisions continue to be refined by patient selection Extended RAS testing (negative predictive biomarker) MSI-H/MMR-D testing (positive predictive biomarker) HER2 testing (positive predictive biomarker)

52 Thank