seminar on first line management of pancreatic carcinoma.4.2024.pptx

regarding mangement of pancreas

1. First line management of metastatic ca pancreas. Dr Mallupattu Sumanth Kumar , Medical Oncologist, [email protected]

2. Standard of care: FOLFIRINOX Gemcitabine +Nab-paclitaxel 6 months

3. FOLFIRINOX improved OS ( median 11.1 versus 6.8 months , hazard ratio [HR] 0.57, 95% CI 0.45-0.73),

4. MPACT TRIAL DESIGN extended follow-up ( median OS 8.7 versus 6.6 months , HR 0.72, 95% CI 0.62-0.83),

5. In the past decade, two combination chemotherapy regimens, fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel and gemcitabine, have emerged as first-line standard of care for patients with metastatic pancreatic ductal adenocarcinoma. In phase 3 trials, FOLFIRINOX and nab-paclitaxel and gemcitabine have each been compared with gemcitabine alone, but the two regimens have never been compared head to head , leaving uncertainty about the optimal first-line treatment option. In a phase 1/2 trial (NCT02551991) liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX), demonstrated promising antitumour activity in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma.

6. Liposomal irinotecan is a liposomal formulation that encapsulates irinotecan, a topoisomerase I inhibitor , in a lipid bilayer vesicle. Encapsulation allows irinotecan to remain in circulation for longer than unencapsulated (free) irinotecan before conversion to its active metabolite , SN-38. Thus, at equivalent doses, liposomal irinotecan demonstrates higher and sustained intratumoural levels of irinotecan and SN-38 relative to free irinotecan.

7. NAPOLI 3: Study Design Wainberg. ASCO GI 2023. Abstr LBA661 . Randomized, open-label phase III trial (data cutoff: July 23, 2022) Patients with metastatic PDAC and no previous treatment in the metastatic setting; metastatic disease diagnosis ≤6 wks before screening;ECOG PS 0/1 (N = 770) Liposomal Irinotecan 50 mg/m 2 + 5-FU 2400 mg/m 2 + L eucovorin 400 mg/m 2 + Oxaliplatin 60 mg/m 2 Days 1 and 15 of a 28-day cycle Gemcitabine 100 0 mg/m 2 + Nab-paclitaxel 125 mg/m 2 Days 1, 8, and 15 of a 28-day cycle Stratified by ECOG PS (0 vs 1); region (North America vs ROW); liver metastases (yes vs no) Primary endpoint: OS Secondary endpoints: PFS and ORR per investigator using RECIST v1.1, safety Until PD unacceptable toxicity, or study withdrawal NAPOLI3

8. NAPOLI 3: Baseline Characteristics Wainberg. ASCO GI 2023. Abstr LBA661 . Characteristic NALIRIFOX (n = 383) Gemcitabine + Nab-paclitaxel (n = 387) Median age, yr (range) 64 (20-85) 65 (36-82) Male, % 53.3 59.4 White, % 82.2 83.7 ECOG PS 1, % 58.0 56.6 Number of metastatic sites, 1/2/≥3, % 29.8/31.3/38.9 35.7/27.9/36.4 Liver metastases, % 80.2 80.4 Geographic region, % North America East Asia Rest of the world 31.3 2.9 65.8 31.5 2.8 65.6 Main pancreatic tumor location, % Head Other 38.4 61.6 40.3 59.7 Baseline CA 19-9, % <37 U/mL ≥37 U/mL 15.7 83.8 18.3 81.7 Median time from diagnosis of metastatic PDAC until randomization, wk (range) 3.00 (0.60-9.10) 3.57 (0.40-10.90)

9. NAPOLI: OS (Primary Endpoint) Wainberg. ASCO GI 2023. Abstr LBA661 . Reproduced with permission. Median (95%CI) 11.1 (10.0, 12.1) 9.2 (8.3, 10.6) HR (95%CI) 0.83 (0.70, 0.99) P Value .04 Arm NALIRIFOX Gem + Nab-P OS (%) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 383 387 337 345 308 298 274 261 241 218 209 179 162 140 98 80 59 50 32 28 13 15 7 10 2 3 1 1 No. at risk: NALIRIFOX Gem + Nab-P Time (months)

10. NAPOLI: OS in Subgroups Wainberg. ASCO GI 2023. Abstr LBA661 . Reproduced with permission. Subgroup Overall Presence of liver metastases at baseline Yes No Number of metastatic sites 1 2 ≥3 Baseline ECOG performance status 1 Region North America Rest of the world Main pancreatic tumor location Head Other Baseline CA 19-9 <37 U/mL ≥37 UmL Race White Sex Male Female Age <65 years ≥65 years Gem + Nab-P events/patients 285 / 387 242 / 309 43 / 78 92 / 138 83 / 108 110 / 141 112 / 171 173 / 216 94 / 122 191 / 265 116 / 156 169 / 231 45 / 71 240 / 316 240 / 324 175 / 230 110 / 157 130 / 191 155 / 196 NALIRIFOX events/patients 259 / 383 220 / 309 39 / 74 75 / 114 87 / 120 97 / 149 97 / 168 162 / 215 85 / 120 174 / 263 97 / 147 162 / 236 34 / 60 223 / 321 218 / 315 139 / 204 120 / 179 127 / 193 132 / 190 HR (95% CI) 0.83 (0.70, 0.99) 0.82 (0.68, 0.98) 0.89 (0.57, 1.37) 0.98 (0.72, 1.32) 0.89 (0.65, 1.20) 0.69 (0.52, 0.90) 0.75 (0.57, 0.98) 0.91 (0.73, 1.13) 0.79 (0.59, 1.06) 0.86 (0.70, 1.05) 0.86 (0.65, 1.12) 0.83 (0.67, 1.02) 0.75 (0.48, 1.17) 0.84 (0.70, 1.01) 0.84 (0.70, 1.01) 0.82 (0.66, 1.02) 0.88 (0.68, 1.14) 0.92 (0.72, 1.17) 0.77 (0.61, 0.97) 0.0 0.5 1.0 1.5 2.0 Gem + Nab-P better NALIRIFOX better NAPOLI3

11. NAPOLI: PFS per Investigator Wainberg. ASCO GI 2023. Abstr LBA661 . Reproduced with permission. Median (95%CI) 7.4 (6.0, 7.7) 5.6 (5.3, 5.8) HR (95%CI) 0.69 (0.58, 0.83) P Value <.0001 Arm NALIRIFOX Gem + Nab-P PFS (%) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 383 387 271 267 210 182 164 112 122 60 87 38 61 19 39 6 20 3 9 1 5 4 No. at risk: NALIRIFOX Gem + Nab-P Time (months) NAPOLI3

12. NAPOLI: PFS in Subgroups Wainberg. ASCO GI 2023. Abstr LBA661 . Reproduced with permission. NALIRIFOX events/patients 249 / 383 211 / 309 38 / 74 66 / 114 88 / 120 95 / 149 99 / 168 150 / 215 78 / 120 171 / 263 93 / 147 156 / 236 33 / 60 214 / 321 203 / 315 127 / 204 122 / 179 127 / 193 122 / 190 Subgroup Overall Presence of liver metastases at baseline Yes No Number of metastatic sites 1 2 ≥3 Baseline ECOG performance status 1 Region North America Rest of the world Main pancreatic tumor location Head Other Baseline CA 19-9 <37 U/mL ≥37 UmL Race White Sex Male Female Age <65 years ≥65 years Gem + Nab-P events/patients 259 / 387 213 / 309 46 / 78 89 / 138 67 / 108 103 / 141 111 / 171 148 / 216 72 / 122 187 / 265 108 / 156 151 / 231 44 / 71 215 / 316 221 / 324 154 / 230 105 / 157 128 / 191 131 / 196 HR (95% CI) 0.69 (0.58, 0.83) 0.72 (0.59, 0.87) 0.57 (0.36, 0.88) 0.66 (0.48, 0.92) 0.83 (0.60, 1.15) 0.60 (0.45, 0.79) 0.54 (0.41, 0.72) 0.83 (0.66, 1.05) 0.57 (0.40, 0.80) 0.73 (0.59, 0.90) 0.71 (0.53, 1.94) 0.67 (0.54, 0.85) 0.56 (0.35, 0.90) 0.71 (0.58, 0.86) 0.69 (0.57, 0.84) 0.69 (0.54, 0.87) 0.71 (0.54, 0.92) 0.74 (0.57, 0.95) 0.65 (0.50, 0.84) 0.0 0.5 1.0 1.5 2.0 Gem + Nab-P better NALIRIFOX better NAPOLI3

13. NAPOLI 3: Tumor Response Wainberg. ASCO GI 2023. Abstr LBA661 . Response NALIRIFOX (n = 383) Gemcitabine + Nab-paclitaxel (n = 387) Objective response rate, % (95% CI) 41.8 (36.8-46.9) 36.2 (31.4-41.2) Best overall response, % Complete response Partial response Stable disease Progressive disease Not evaluable 0.3 41.5 25.8 9.9 22.5 0.3 35.9 26.1 14.5 23.3 NAPOLI3

14. NAPOLI 3: Overall Safety Wainberg. ASCO GI 2023. Abstr LBA661 . TEAE NALIRIFOX (n = 370) Gemcitabine + Nab-paclitaxel (n = 379) Median treatment duration, wk (range) 24.29 (0.4-100.9) 17.57 (0.7-81.7) All-grade TEAEs, % Related to treatment 99.7 95.1 99.2 92.9 Grade ≥3 TEAEs, % Related to treatment 87.0 70.8 86.0 68.1 Serious TEAEs, % Related to treatment 54.3 26.5 51.5 19.0 TEAEs leading to death, % Related to treatment 5.9 1.6 6.1 2.1 NAPOLI3

15. NAPOLI 3: Select TEAEs Wainberg. ASCO GI 2023. Abstr LBA661 . TEAEs in ≥10% of Patients, % NALIRIFOX (n = 370) Gemcitabine + Nab-paclitaxel (n = 379) Any Grade Grade 3/4 Any Grade Grade 3/4 Hematologic Neutropenia/neutrophil count decreased/ febrile neutropenia Anemia Thrombocytopenia/platelet count decreased 29.5/20.5/2.4 26.2 13.5/10.5 14.1/9.7/2.4 10.5 0.8/0.8 31.9/18.7/2.6 40.4 22.7/17.9 24.5/13.5/2.4 17.4 3.7/2.4 Nonhematologic Diarrhea Nausea Vomiting Hypokalemia Peripheral neuropathy Peripheral sensory neuropathy Paresthesia Pyrexia 70.5 59.5 39.7 31.6 17.8 15.1 11.9 10.5 20.3 11.9 7.0 15.1 3.2 3.5 0.3 0.8 36.7 42.7 26.4 12.9 17.4 13.5 8.7 23.0 4.5 2.6 2.1 4.0 5.8 2.9 0.5 1.6 NAPOLI3

16. NAPOLI 3: Conclusions In the phase III NAPOLI 3 study, first-line NALIRIFOX statistically significantly prolonged OS and PFS vs gemcitabine + nab-paclitaxel in patients with metastatic PDAC The OS and PFS benefits were generally consistent across various patient subgroups NALIRIFOX showed manageable safety profile and no new safety signals were observed NAPOLI 3 had fewer restrictions on eligibility than most phase 3 pancreatic cancer trials, for example no upper age restrictions and no exclusion for patients with clinical ascites. Wainberg. ASCO GI 2023. Abstr LBA661 . NAPOLI3

17. First line management of Her2 positive metastatic gastric and GE junction tumors

18. KEYNOTE-811 : Background Trastuzumab with chemotherapy (fluoropyrimidine and platinum) is standard first-line therapy for HER2+ metastatic gastric or gastroesophageal junction cancer Phase II results suggest that addition of pembrolizumab to trastuzumab/ chemotherapy has manageable safety and antitumor activity in this setting Phase III KEYNOTE-811 trial evaluated safety and efficacy of adding pembrolizumab to trastuzumab/chemotherapy in unresectable or metastatic HER2+ gastric or gastroesophageal junction cancer protocol-specified first interim analysis that assessed ORR after first 260 patients had follow-up ≥8.5 mo ; superiority boundary P = .002 (1 sided) 1. Janjigian . Lancet Oncol. 2020;21:821. 2. Rha . ASCO 2020. Abstr 3081. 3. Janjigian ASCO 2021. Abstr 4013. Slide credit: clinicaloptions.com KEYNOTE-811

19. Randomized, double-blind, placebo-controlled phase III study Efficacy analysis: first 264 patients enrolled; safety analysis: 433 patients who received ≥1 dose of study medication Primary endpoints: OS, PFS per RECIST v1.1 by BICR Secondary endpoints: ORR and DoR per RECIST v1.1 by BICR, safety KEYNOTE-811 Interim Analysis : Study Design Patients with HER2+ advanced gastric or GEJ adenocarcinoma, no prior therapy in advanced setting (N = 692) Pembrolizumab 200 mg IV Q3W + Trastuzumab 6 mg/kg IV Q3W + FP or CAPOX* Placebo IV Q3W + Trastuzumab 6 mg/kg IV Q3W + FP or CAPOX* Stratified by geographic region, PD-L1 CPS, chemotherapy choice Janjigian ASCO 2021. Abstr 4013. Up to 35 cycles or until disease progression, unacceptable toxicity, or study withdrawal *Trastuzumab 8 mg/kg loading dose. FP: 5-fluorouracil 800 mg/m 2 IV Days 1-5 Q3W + cisplatin 80 mg/m 2 IV Q3W CAPOX: capecitabine 1000 mg/m 2 BID Days 1-14 Q3W + oxaliplatin 130 mg/m 2 IV Q3W Slide credit: clinicaloptions.com KEYNOTE-811

20. KEYNOTE-811 Interim Analysis : Baseline Characteristics Characteristic Efficacy Population Pembrolizumab (n = 133) Placebo (n = 131) Median age, yr (range) 62 (19-84) 61 (32-83) Male, n (%) 112 (84) 103 (79) Region of enrollment Australia/EU/Israel/N America Asia Rest of world 41 (31) 40 (30) 52 (39) 45 (34) 39 (30) 48 (37) ECOG PS 1, n (%) 68 (51) 72 (5Stomach as 5) Stomach as primary location 96 (72) 89 (68) Histological subtype Diffuse Intestinal Indeterminate 28 (21) 81 (61) 24 (18) 26 (20) 63 (48) 42 (32) PD-L1 CPS ≥1 117 (88) 111 (85) HER2 status IHC 2+, ISH positive IHC 3+ 24 (18) 109 (82) 28 (21) 103 (79) Chemotherapy CAPOX FP 114 (86) 19 (14) 115 (88) 16 (12) Janjigian ASCO 2021. Abstr 4013. Slide credit: clinicaloptions.com KEYNOTE-811

21. KEYNOTE-811 Interim Analysis : Efficacy Outcome Efficacy Population Pembrolizumab (n = 133) Placebo (n = 131) ORR, % (95% CI) 74.4 (66.2-81.6) 51.9 (43.0-60.7) ORR difference* 22.7 (11.2-33.7); P = .00006 DCR, % (95% CI) 96.2 (91.4-98.8) 89.3 (82.7-94.0) Best response, n (%) CR PR SD PD Not evaluable Not assessed 15 (11) 84 (63) 29 (22) 5 (4) 4 (3) 64 (49) 49 (37) 7 (5) 2 (2) 5 (4) Duration of response † Median, mo (range) ≥6 mo duration, % ≥9 mo duration, % (n = 99) 10.6 (1.1+ to 16.5+) 70.3 58.4 (n = 68) 9.5 (1.4+ to 15.4+) 61.4 51.1 Size reduction from baseline, n (%) Any decrease ≥80% decrease (n = 124) ‡ 97 32 (n = 122) ‡ 90 15 Janjigian ASCO 2021. Abstr 4013. *Calculated using Mietten and Nurminen method; stratified by randomization stratification factors. † Calculated in patients with CR or PR as best response. ‡ Calculated in patients with measurable disease at baseline and at least 1 post baseline measurement. Slide credit: clinicaloptions.com KEYNOTE-811

22. Immune-Mediated AEs and Infusion Reaction,* % Pembrolizumab (n = 217) Placebo (n = 216) Any grade 34 21 Gr ≥3 10 3 Serious 9 3 Led to death 1 <1 Led to discontinuation 6 2 Any Gr ≥3 Any Gr ≥3 Incidence ≥ 2 patients Infusion reactions Pneumonitis Colitis Hypothyroidism Hyperthyroidism Hypophysitis Hepatitis Severe skin reactions 18 5 5 5 4 1 1 1 3 1 3 <1 1 1 13 1 2 3 3 1 1 2 KEYNOTE-811 Interim Analysis : Safety AEs, % Pembrolizumab (n = 217) Placebo (n = 216) Any grade 97 98 Gr ≥3 57 57 Serious 31 38 Led to death 3 5 Led to discontinuation 24 26 Any Gr ≥3 Any Gr ≥3 Incidence >20% Diarrhea Nausea Anemia Decreased appetite Vomiting Decreased platelets Fatigue Decreased neutrophils Peripheral neuropathy Increased AST 53 49 41 31 31 24 24 24 23 21 7 5 9 2 5 8 4 7 3 <1 44 44 44 32 27 28 20 25 19 13 8 6 9 4 2 7 3 7 1 <1 Janjigian ASCO 2021. Abstr 4013. *Events considered regardless of attribution to treatment by investigator. Related terms included in addition to specific terms listed . Slide credit: clinicaloptions.com KEYNOTE-811

23. KEYNOTE-811: Conclusions Adding pembrolizumab to trastuzumab/CT led to a 22.7% improvement in ORR vs placebo + trastuzumab/CT as first-line treatment for patients with advanced HER2+ gastric or gastroesophageal junction cancer Responses with pembrolizumab + trastuzumab/CT were deeper and more durable than those achieved with placebo + trastuzumab/CT Safety profile was similar between treatment arms with no unexpected safety concerns associated with pembrolizumab. Slide credit: clinicaloptions.com Janjigian ASCO 2021. Abstr 4013. KEYNOTE-811

24. KEYNOTE-811:3 rd Interim analysis Conclusions At median follow-up 38·4 months median PFS was 10·0 months (8·6–12·2) versus 8·1 months (7·1–8·6; HR 0·73 [0·61–0·87]). Median overall survival: 20·0 months vs 16·8 months ( HR 0·84 [0·70–1·01]), but did not meet prespecified criteria for significance and will continue to final analysis. Slide credit: clinicaloptions.com Janjigian ASCO 2021. Abstr 4013. KEYNOTE-811

25. C heckpoint inhibitors as perioperative therapy for gastric and GE carcinoma

26. DANTE- Atezolizumab KEYNOTE 585- Pembrolizumab MATTERHORN- Durvalumab

27. Phase 2 DANTE Trial: Histopathologic Regression according to PD- L1- Expression Arm A: FLOT + Atezolizumab ( n =146) Arm B: FLOT ( n =149) Regression grading according to Becker Complete response (no residual tumor) 35 (24%) 23 (15%) Subtotal response (<10% residual tumor) 36 (25%) 35 (24%) Partial response (10%- 50% residual tumor) 40 (27%) 37 (25%) Minor response (>50% residual tumor) 27 (19%) 40 (27%) No response 2 (1%) 7 (5%) Missing 6 (4%) 7 (5%) Regressing grading in subgroups < CPS 1 (n=64/58): CR & CR/SR 15 (23%) & 29 (45%) 9 (16%) & 17 (29%) ≥ CPS 1 (n=82/88): CR & CR/SR 20 (24%) & 42 (51%) 13 (15%) & 40 (31%) ≥ CPS 5 (n=40/41): CR & CR/SR 11 (28%) & 22 (56%) 8 (20%) & 18 (44%) ≥ CPS 10 (n=27/26): CR & CR/SR 9 (33%) & 18 (67%) 3 (12%) & 10 (39%) MSI/MMRd (n=8/15): CR & CR/SR 5 (63%) & 6 (76%) 4 (27%) & 7 (47%) Lorenzen S, Al- Batran SE JCO in press pCR according to PD-L1 CPS Fleitas T. & Lorenzen S.

28. Fleitas T. & Lorenzen S. pCR Phase 3 KEYNOTE- 585 study: Pembro + Chemo vs Chemo Primary endpoints pCR and EFS Main Cohort (XP or FP) n= 804; Median Follow- Up: 47.7 months EFS Shitara K et al. ESMO 2023; # 7504 Improvement of the pCR Δ 10.9%; P < 0.0001; Difference in EFS no significant. HR 0.81; P = 0.0198; median 44.4 vs 25.4 months OS XP= Capecitabine + cisplatin; FP= 5-Fluorouracil + cisplatin Main Cohort: 79% stomach Asia (47%) CPS ≥ 1 73%

29. Phase 3 KEYNOTE- 585 study: Pembro + Chemo vs Chemo pCR EFS Conclusion: IO plus preop. CTX improves pCR Δ 10.6% FLOT +Pembro subgroup: results for pCR, Downstaging, EFS/OS pending Primary Endpoints Main (n=804) + FLOT Cohort (n=203) Shitara K et al. ESMO 2023; # 7504 Fleitas T. & Lorenzen S. Main + FLOT: 75% stomach Asia (38%) CPS ≥ 1 73% OS Notas del ponente 2023-10-24 13:43:27 ------------------------------------------- - .

30. Phase 3 MATTERHORN study: Durva +FLOT vs FLOT Durvalumab + FLOT: 68% stomach Asia (19%) TAP ≥ 1 90% Secondary endpoint central review pCR and near-complete pCR Al- Batran SE et al. ESMO 2023; # 2059 Near-complete pCR pCR Similar improvement of pCR rates and downstaging in Matterhorn and DANTE with additional IO ( ∆ approx. 10%)

31. Does addition of immune checkpoint inhibitors improve pCR? KEYNOTE 585 & MATTERHORN KEYNOTE 585 MATTERHORN FP or FLOT chemo Chemo-pembro FLOT FLOT-durva pCR 2.4% 13.0% 7 % 19% Δ10.6% (7.4- 14.0) ∆12% OR : 3.08 (2.03–4.67) p<0.00001 Mandard et al, Cancer, 1994 Ryan et al, Histopathology 2005 Elizabeth Smyth MD

32. Content of this presentation is copyright and responsibility of the author. Permission is required for re- use. Degree of response in lymph nodes differentiates survival pCR – it’s not just the primary that matters Elizabeth Smyth MD Also within lymph nodes, degree of response to chemotherapy is predictive Negative nodes post chemotherapy = survival to non- involved nodes Partial response in lymph nodes > survival than no response Smyth, Valeri et al, J Clin Oncol 2016 Liu et al, JCRCO 2023 Lymph nodes can be discordant with primary in biomarker status ~27% discordant in PD- L1 expression…

33. Phase 3 studies on checkpoint inhibitors as perioperative therapy for gastric and oesophageal carcinoma No trial showed an improvement in the overall survival yet Fleitas T. & Lorenzen S.

34. Conclusions: NALFIRINOX regimen can used as first line option in metastatic patients Addition of pembrolizumab to anti Her2 & chemo have improved ORR, PFS and trend towards OS in advanced gastric & GE junction tumors, further analysis is ongoing. Perioperative immunotherapy has provided improved pCRin advanced gastric & GE tumors, but yet failed to show statistically significant EFS benefit, no OS benefit. Doublet chemotherapy regimen- capox / folfox still remains standard of care in advanced gastric & GE tumors.. Addition of docetaxel to doublet failed to show OS benefit and also associated with increased toxicities.