Upper GI - RK

Question 1

KEYNOTE-811
Gastric

Answer 1

P: Metastatic/unresectable adeno of stomach or GE junction, HER2+, 1st line tx

I: Arm 1: Placebo vs Pembro 200 mg q3 weeks, on top of trastuzumab and CIS+5FU or CAPOX.

O: OS, PFS primary endpoints not reported. Objective response was observed in 74.4% vs 51.9% of patients, with complete response in 11.3% vs 3.1%.

Question 2

CROSS trial (PRE-OP)

Answer 2

P: Esophageal/ GE Junction T2 or greater, LN positive (not gastric)

I: Carboplatin AUC 2 weekly x 5 and Paclitaxel 50mg/m2 weekly x 5 with RT 41 Gy over 23 fractions –> surgery

C: surgery only

O: 5 year OS 47% VS 37%.
HR for adeno 0.73.
HR for squamous 0.45.

Question 3

MAGIC trial (Peri-OP)

Answer 3

P: Esophageal, GE Junction, Gastric

I:
3 cycles of:
Epirubucin 50 mg/m2 q3wk +
Cisplatin 60 mg/m2 q3wk +
5FU 200 mg/m2 d1-d21 (or Cape d1-21)

Surgery –> 3 cycles

C: Surgery

O: 5 year OS 36% vs 23%

Question 4

FLOT4 trial (periop)

Answer 4

P: GE Junction, esophageal, Gastric
I:
4 cycles of
5FU 2600 mg/m2 over 2 days q2wk
leucovorin 85 mg/m2 q2wk
Oxaliplatin 85 mg/m2 q2wk
Docetaxel 50 mg/m2 q2wk

surgery
4 more cycles of chemo

C: ECF

o:
5 year OS 45% FLOT vs 36% ECF/X

Question 5

INT 0016 TRIAL
Macdonald Protocol (adjuvant)

Answer 5

P: Gastric Ca

I:
5FU + LV d1-5, 4 weeks after
RT 45 Gy/25# (5FU/LV given first 4 and last 3 days of RT). Then 4 weeks later, 5FU/LV d1-5 q28 days x 2 cycles

C: Obs
O: 5 year OS 40% vs 25%

Question 6

Checkmate 577

Answer 6

P: Resected (R0) stage II or III esophageal or GE junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease
I: Nivolumab 240 mg every 2 weeks for 16 weeks, followed by nivolumab 480 mg every 4 weeks x total duration 1 year
C: Obs
O:
DFS adeno HR 0.75
DFS squam HR 0.61

Question 7

IMbrave 150 (HCC)

Answer 7

Phase 3, NEJM 2020, 1st-line
P - Advanced, unresectable HCC, ineligible for locoregional therapies. No prior systemic therapy. CPA. N = 501
I - Atezolizumab + Bevacizumab IV q 3 weeks
C - Sorafenib 400mg PO BID
O - Median OS 19.2m v 13.4m (HR 0.66, p < 0.001)
mPFS 6.9m v 4.3m (HR 0.65, p< 0.001)
Gr 3/4 AEs in 43% (Atezo/Bev -> hypertension, hepatotoxicity, proteinuria) v 46% (Sorafenib -> hypertension, HFS, diarrhea, hepatotoxicity)

Question 8

HIMALAYA (HCC)

Answer 8

Phase 3, NEJM 2022, 1st-line
P - BCLC B or C HCC ineligible for local therapy, no prior systemic therapy. CPA. Patients with ascites, PVT excluded (N = 1171)
I - Tremelimumab x 1 dose + Durvalumab IV q4w OR Durvalumab IV q4w
C - Sorafenib 400mg PO BID
O - mOS 16.4m (Trem + Durva) v. 16.56m (Durva) v. 13.77m (Sorafenib). HR Trem + Durva v. Sorafenib 0.78 (p= 0.0035). HR Durva v Sorafenib 0.86
3/4 AEs: Trem + Durva 50.5% (diarrhea, hepatotoxicity, lipase increase), 37.1% Durva (hepatotoxicity, lipase increase, anemia), and 52.4% sorafenib (HFS, diarrhea, HTN)
Note endpoint for Trem + Durva v Sorafenib was for superiority, for Durva v Sorafenib was for non-inferiority. Both respective endpoints were met.

Question 9

Kudo et al. (HCC)

Answer 9

Phase 3, Lancet 2018, 1st-line
NON-INFERIORITY TRIAL
P - BCLC B or C, unresectable HCC, no prior systemic therapy, CPA. Excl. patients with >50% liver occupation, invasion of bile duct, PVT. N = 954
I - Lenvatinib 12mg PO daily for wt > 60kg, 8mg PO daily for wt <60kg.
C - Sorafenib 400mg PO BID
O - mOS Len 13.6m and was non-inferior to sorafenib which had mOS 12.3m, HR 0.92
Gr3/4 AEs Len 57% (HTN, Hepatotoxicity, anorexia)
Sorafenib 49% (HFS, HTN, hepatotoxicity)

Question 10

SHARP (HCC)

Answer 10

Phase 3, NEJM 2008, 1st-line
P - Advanced, unresectable HCC, no prior systemic therapy. Ineligible for locoregional therapies. ECOG <=2, CP A. N = 602
I - Sorafenib 400mg PO BID
C - Placebo
O - mOS 10.7m v 7.9m, HR 0.69, p < 0.001
Gr 3/4 AEs Sora 80% (HFS, diarrhea, fatigue, anorexia)
Placebo 52% (fatigue, diarrhea, rash)

Question 11

RESOURCE (HCC)

Answer 11

Phase 3, Lancet 2017, 2nd-line
P - BCLC B or C, unresectable HCC, ineligible for locoregional therapies, CPA. Progressed on sorafenib. N = 573
I - Regorafenib 160mg PO daily, weeks 1-3 out of 4
C - Placebo
O - mOS 10.6m v 7.8m, HR 0.63, p< 0.0001
AEs Regorafenib gr 3/4 50% (HFS, HTN, fatigue)

Question 12

Abou-Alfa et al. (HCC)

Answer 12

Phase 3, NEJM 2018, 2nd or 3rd-line
P - Advanced, unresectable HCC, previously treated with sorafenib. CP A. Could have up to 2 previous systemic therapies. N = 707
I - Cabozantinib 60mg PO daily
C - Placebo
O - mOS 10.2m v 8m, HR 0.76
mPFS 5.2m v 1.9m, HR 0.44
Gr 3/4 AEs Cabo 68% (HFS, HTN, hepatotoxicity, fatigue, diarrhea)

Question 13

REACH-2 (HCC)

Question 14

PRODIGE-24 (Pancreas)

Answer 14

P - Resectable PDAC, ECOG 0 - 1
I - mFOLFIRINOX (note difference with FOLFIRINOX, bolus is omitted, irinotecan 150mg/m2 as opposed to 180mg/m2)
C- Gemcitabine
O - DFS 21.6m v 12.8m. mOS 54.4m v 35.0m

Question 15

APACT (Pancreas)

Answer 15

P - Resectable PDAC. ECOG 0 -1
I - Gem + Nab-paclitaxel
C - Gem
O - DFS 19.4m v 18.8m (NS). OS 41.8m v 37.7m (sig)

Question 16

ESPAC-4 (Pancreas)

Answer 16

P - Resectable PDAC. PS <= 2
I - Gem + Cape
C - Gem
O - OS 28.8m v. 25.5m (p = 0.032).

Question 17

CONKO-001 (Pancreas)

Answer 17

P - Resectable PDAC, Karnosfky >= 50%
I - Gem
C - Observation
O - DFS 13.4m v 6.7m (sig), OS 22.8m v 20.2m (sig)

Question 18

PREOPANC (Pancreas)

Answer 18

P - Resectable and Borderline resectable PDAC
I - Neoadjuvant CRT with gemcitabine (3 cycles gem with 36Gy in 15# given during second cycle) followed by four cycles adjuvant gemcitabine
C- Surgery then 6 cycles of adjuvant gemcitabine
O - mOS 15.7m v 14.3m overall. BR-PDAC subgroup mOS 17.6m v 13.2m. Improved R0 resection rate 71% v 40% (79% v 13% for BR-PDAC)

Question 19

ACCORD 11 (Pancreas)

Answer 19

P - metastatic pancreas cancer. 1st-line
I - FOLFIRINOX
C - Gemcitabine
O - mOS 11.2 v 6.8m (sig). RR 31.6% v 9.4%

Question 20

MPACT (Pancreas)

Answer 20

P - metastatic pancreas cancer, 1st-line
I - Gem + Nab-Paclitaxel
C - Gem
O - mOS 8.7m v 6.7m. RR 23% v 7%

Question 21

POLO (Pancreas)

Answer 21

P - Met pancreas cancer. Germline BRCA1/2
I - Maintenance olaparib in patients who did not progress on first-line platinum-based chemotherapy
C - Placebo
O - PFS 7.4 v 3.8m (sig). mOS 18.9mv 18.1m (NS). No difference in QOL