ASCO 2014 update in GI cancer

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ASCO 2014 update in GI cancer treatment
Kanwal Pratap Singh Raghav, MD

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ASCO 2014 update in GI cancer

  1. 1. ASCO 2014: UPDATES IN GASTROINTESTINAL ONCOLOGY Annual Updates on Breakthroughs in Hematology & Oncology (AUBHO) 2014 Kanwal Pratap Singh Raghav, MD The University of Texas M.D. Anderson Cancer Center, Houston, TX 30th August 2014
  2. 2. ARCHIVES: 1964-65
  3. 3. CALGB/SWOG 80405 Alan P. Venook et al. Abstract: LBA3
  4. 4. CALGB/SWOG 80405 Alan P. Venook et al. Abstract: LBA3 ✤ In patients with KRAS-WT metastatic CRC where we have option of using two biologics in first line (anti-EGFR and anti-VEGF), does the choice really matter?
  5. 5. CALGB/SWOG 80405: OVERVIEW Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). FOLFOX (73%) ✤ Primary Endpoint: OS ✤ Ho = 22 v. 27.5 m ✤ N = 1137
  6. 6. CALGB/SWOG 80405: RESULTS Similar PFS, Different AE/QoL (Resected disease: Median OS ~ 5.5 yr)
  7. 7. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  8. 8. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  9. 9. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  10. 10. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  11. 11. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  12. 12. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  13. 13. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  14. 14. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  15. 15. CALGB/SWOG 80405: PAST & PRESENT GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99) NO 16966: FOLFOX/ XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07) CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01) PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04) FOLFOX FOLFIRI C + FOLFIRI FOLFIRI B + FOLFOX/XELOX FOLFOX/XELOX P + FOLFOX FOLFOX Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
  16. 16. SWOG 80405: LESSONS LEARNED! Chemo-Bev equivalent to Chemo-Cetux in 1st-line mCRC Rx of KRAS-WT (12/13) tumors. Median OS in patient with resected mCRC ~ 5.5 yrs. ✤ ? Clinical applicability to extended RAS Mutants. ✤ ? FIRE-3: Better OS with FOLFIRI + C as 1st-line. ✤ ? PEAK: Better OS with FOLFOX + P as 1st-line. ✤ ? Sequential question unanswered (PDT rates ?). ✤ ? EPOC: Inferior PFS in resectable group. ✤ FOLFOX is preferred first line chemotherapy in the US. ✤ Future: Think ahead and homogenize population using molecular profiles.
  17. 17. ADORE TRIAL TAE WON KIM ET AL. (ABSTRACT 3502) In patients with rectal cancer who have received standard of care pre-operative chemoradiotherapy followed by surgery, is post-operative chemotherapy with FOLFOX better than 5FU alone in pathologic stage II/III disease in delaying recurrence? Primary Endpoint: 3-yr. DFS. ✤ Subgroup effect: Stage III & poor neoadjuvant therapy response, LVI -ve ✤ FOLFOX: BMD, Neuropathy, Fatigue
  18. 18. CAIRO-3 TRIAL MIRIAM KOOPMAN ET AL. (ABSTRACT 3504) In patients with metastatic CRC, after 6 cycles of CAPOX-B does maintenance therapy with Cape + Bev improve PFS? Primary Endpoint: PFS2 [Re-intro: 60% (o) v. 47% (m)]
  19. 19. ARCHIVES: 1964-65
  20. 20. STORM TRIAL Jordi Bruix et al. Abstract: 4006
  21. 21. STORM TRIAL Jordi Bruix et al. Abstract: 4006 ✤ In patients hepatocellular cancer who have undergone resection or local ablation and are without residual disease, does adjuvant sorafenib decrease recurrence?
  22. 22. STORM TRIAL: OVERVIEW A phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC). Child-Pugh A/B7 (2-3% only) & ECOG PS 0 Background: 5-yr OS 50-80% (Patient selection) & Sorafenib active in metastatic setting HCC (N = 1114) No Residual Disease Sorafenib 4 years Placebo 4 years Surgery or Ablation Primary Endpoint: RFS * Sorafenib 400mg BID
  23. 23. STORM TRIAL: RESULTS No subgroup effect Similar OS (HR=0.99) TEAE significant (DC 25%) (Dose Δ 80%) Rx duration ~12.5 (v. 22 m)
  24. 24. STORM: PAST & PRESENT Meta-analysis (2001) N = 180 (3 PTs) Radical resection and IA Epi + PO Tegafur IA Epi + IV Epi IV Epi Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis) Surgery Adjuvant Rx Ono et al. Cancer 2001
  25. 25. STORM: PAST & PRESENT Meta-analysis (2001) N = 180 (3 PTs) Radical resection and IA Epi + PO Tegafur IA Epi + IV Epi IV Epi Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis) Surgery Adjuvant Rx Ono et al. Cancer 2001
  26. 26. STORM: PAST & PRESENT Meta-analysis (2001) N = 180 (3 PTs) Radical resection and IA Epi + PO Tegafur IA Epi + IV Epi IV Epi Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis) Surgery Adjuvant Rx Ono et al. Cancer 2001
  27. 27. STORM: LESSONS LEARNED! Adjuvant Sorafenib does not improve RFS in locally resected or ablated HCC. ✤ Another lesson in distinctive adjuvant & metastatic setting: ✤ ? Micro v. Macro metastatic disease & distinct biology ✤ ? Angiogenesis (Adjuvant) ✤ ? Cytostatic v. Cytocidal drug ✤ 5-yr. OS in patient with resected or ablated HCC ~ 70%. ✤ Drug toxicity profile very important in adjuvant settings. ✤ Future: Molecular characterization and biology oriented therapy and risk stratification ! Ono et al. Cancer 2001
  28. 28. LAP 07 STUDY Florence Huguet et al. Abstract: 4001
  29. 29. LAP 07 STUDY Florence Huguet et al. Abstract: 4001 ✤ In patients with locally advanced pancreatic adenocarcinoma, can use of chemoradiotherapy impact local control and time without systemic therapy?
  30. 30. LAP-07: OVERVIEW Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in international phase III LAP 07 study. Primary Endpoint: OS LAPC (N = 128) R1 Gemcitabine 4 months Gemcitabine + Erlotinib No Progression R2 Cape XRT (N = 136) Same ChemoRx 2 months (N = 133) Retrospective analysis: GERCOR study: 128 patients treated with XRT or chemotherapy after induction chemotherapy (3 months). Median PFS 10.8 v. 7.4 m (P .005) and Median OS 15.0 v. 11.7 m (P .0009). Huguet et al. JCO 2007
  31. 31. LAP-07 TRIAL: RESULTS Toxicity profile similar (except nausea more in CRT arm) Progression site: All v. R2 (32 v. 39% local, 54 v. 52% distant) Median time to CTx reintroduction: 5.2 v. 3.2 m
  32. 32. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  33. 33. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  34. 34. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  35. 35. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  36. 36. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  37. 37. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  38. 38. LAP-07: PAST & PRESENT FFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03). ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%). CRT Arm FFCD Study CTx Arm FFCD Study CTx Arm ECOG Study CRT Arm ECOG Study Continued CTx Arm CRT Arm GERCOR Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007 Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
  39. 39. LAP-07: LESSONS LEARNED! Consolidation CRT after induction CTx in LAPC increases treatment free interval without improvement in overall survival. May play a role in select subset of patients with biology favoring local growth over distant metastases. ✤ ? Is LAPC truly different from metastatic disease. ✤ ? FOLFIRINOX or Gem + Abraxane alter the role of radiation. ✤ Is the duration of induction chemotherapy important to tease out biology ✤ Future: Need for effective systemic therapies and predictive biomarkers of response to both chemotherapy & radiation!
  40. 40. RAINBOW TRIAL Shuichi Hironaka et al. Abstract: 4005
  41. 41. RAINBOW TRIAL Shuichi Hironaka et al. Abstract: 4005 ✤ In patients with advanced gastric or gastroesophageal cancer refractory/intolerant to 5FU and platinum based regimen in first line does addition ramucirumab to second line therapy with paclitaxel improve survival?
  42. 42. RAINBOW: OVERVIEW A Global, Phase III, Randomized, Double-Blind Study of Ramucirumab Plus Paclitaxel versus Placebo Plus Paclitaxel in the Treatment of Metastatic Gastroesophageal Junction and Gastric Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy: Efficacy Analysis in Japanese and Western Patients. Background: AVAGAST study failed to show OS benefit from bevacizumab (median PFS & RR improved). Japanese (0lder, better PS, doublet 1st Rx, gastric): more TEAEs ! Ohtsu et al. JCO 2011; Ciombor et al. CCR 2013
  43. 43. RAINBOW TRIAL: RESULTS More Japanese pts (75% v. 35%) received PDT. Adjusted PDT trends same.
  44. 44. RAINBOW: PAST & PRESENT BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007) BSC Salvage Chemotherapy: Docetaxel/Irinotecan Ramucirumab BSC II REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047) New standard of care. Kang et al. JCO 2012; Fuchs et al. Lancet 2014
  45. 45. RAINBOW: PAST & PRESENT BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007) BSC Salvage Chemotherapy: Docetaxel/Irinotecan Ramucirumab BSC II REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047) New standard of care. Kang et al. JCO 2012; Fuchs et al. Lancet 2014
  46. 46. RAINBOW: PAST & PRESENT BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007) BSC Salvage Chemotherapy: Docetaxel/Irinotecan Ramucirumab BSC II REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047) New standard of care. Kang et al. JCO 2012; Fuchs et al. Lancet 2014
  47. 47. RAINBOW: PAST & PRESENT BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007) BSC Salvage Chemotherapy: Docetaxel/Irinotecan Ramucirumab BSC II REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047) New standard of care. Kang et al. JCO 2012; Fuchs et al. Lancet 2014
  48. 48. RAINBOW: PAST & PRESENT BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007) BSC Salvage Chemotherapy: Docetaxel/Irinotecan Ramucirumab BSC II REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047) New standard of care. Kang et al. JCO 2012; Fuchs et al. Lancet 2014
  49. 49. RAINBOW: LESSONS LEARNED! Ramucirumab + Paclitaxel improves PFS/OS in 2nd-line mG/GEJ cancers refractory to 5FU and Platinum therapy. ✤ ? Is this similar to the story of Bevacizumab (AVAGAST). ✤ ? Why 2nd-line & not 1st-line efficacy. ✤ ? Chemotherapy backbone matters. ✤ ? Validity across populations. ✤ Very heterogenous disease. ✤ Future: Biomarker analysis and comparative angiogenic efficacy! ✤ PDT can confound OS. Choice of control arm critical in studies with OS endpoint. ✤ 1st-line Ramu. + FOLFOX-6: Negative for PFS (HR 0.98). ✤ Apatinib 3rd-line study (v. BSC) (N = 273): OS benefit (HR 0.7) (P = 0.0149)
  50. 50. DISCUSSION

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