Keynote 811 trial update ( ASCO GI Symposium Jan.2024): The trial randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone. Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).
On May 20, 2021, the Food and Drug Administration approved nivolumab for patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy. Efficacy was evaluated in CHECKMATE-577 (link on the comment of 5/16/23 below), a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or GEJ cancers who had residual pathologic disease following concurrent chemoradiotherapy. Patients were randomized (2:1) to receive either nivolumab 240 mg or placebo every 2 weeks for 16 weeks followed by 480 mg of nivolumab or placebo every 4 weeks beginning at week 17 for up to one year of treatment. CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients receiving nivolumab as compared to those on the placebo arm. The median DFS was 22.4 months (95% CI: 16.6, 34.0) versus 11 months (95% CI: 8.3, 14.3), respectively (HR 0.69; 95% CI: 0.56, 0.85; p=0.0003). The DFS benefit was observed regardless of tumor PD-L1 expression and histology.
In November 2023, the FDA approved pembrolizumab + chemo (FP or CAPOX) for advanced/metastatic HER2(-) gastric or GEJ adenocarcinoma. When compared with chemo + placebo, improved OS (12.9 vs. 11.5 mon) and ORR 51 vs42%. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-her2-negative-gastric-or-gastroesophageal-junction
Locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery More than one third of patients with locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery, findings from the Dutch SANO-trial suggest. After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery. Overall, patients who underwent active surveillance had "noninferior overall survival at 2 years," of which study result was presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 on October 20. Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene, Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC). Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death-ligand 1 (PD-L1) inhibitor. Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator's choice of chemotherapy. Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal. Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy. The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough. Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
Pembrolizumab + chemotherapy improves 31-month survival over chemotherapy alone in HER2 (-) metastatic gastric or GEJ adenocarcinoma, regardless of PD-L1 (KEYNOTE-859) www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00515-6/fulltext At Median follow up of 31 months, Median OS was 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo (HR 0.78, 95% CI 0.70-0.87; P < 0.0001). Median PFS was 6.9 mo vs 5.6 mo (HR 0.76, 95% CI 0.67-0.85; P < 0.0001). Results were generally consistent across subgroups, including those by PD-L1 CPS. ORR was 51.3% vs 42.0% (P = 0.00009). Median DOR was 8.0 mo vs 5.7 mo. Grade 3-5 treatment-related AEs occurred in 59.4% of 785 pts treated with pembro + chemo and 51.1% of 787 treated with placebo + chemo; 1.0% and 2.0%, respectively, died of treatment-related AEs. However, this result is somewhat conflicting when compared with those of KEYNOTE-062: The median overall survival of the patients who had pembrolizumab alone was compared with pembrolizumab + chemotherapy. OS of the group w/ CPS 10 or higher: 17.4 vs 10.8 months. In KEYNOTE-859, median overall survival in the CPS 10 or higher group was 15.7 months. In other words, adding chemotherapy to the pembrolizumab in this group (CPS>10) may not be beneficial but more toxic. Furthermore, the OS of the group w/CPS 1 or higher: pembrolizumab + chemo was not better than chemotherapy alone; and pembrolizumab alone was not inferior to chemotherapy.
In Keynote-811 trial where patients with metastatic gastric or GEJ cancer are treated with Pembrolizumab + Herceptin + chemotherapy (CAPOX or FOLFOX), duration of the treatment is up to 2 years or until disease progression or toxicity.
For HER2(-), PD-L1(-) gastric or GEJ cancer, chemotherapy was the treatment. However, now, the standard therapy is combination of Keyruda and chemotherapy based on the KEYNOTE-859 trial. The results from KEYNOTE-859 show the potential of KEYTRUDA plus chemotherapy to improve survival beyond chemotherapy alone for patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, regardless of PD-L1 expression
After neoadjuvant therapy and surgery for esophageal or GEJ adenocarcinoma, nevolymab increased DFS in patients with residual disease. www.nejm.org/doi/full/10.1056/nejmoa2032125
HER-Vaxx which is a B-cell peptide targeted immunotherapy showed 41.5% survival benefit for patients with advanced gastric cancer when compared to the chemotherapy control group (phase 2, HERIZON study).
Thank you Dr. Kim for the great lecture! For patients with resectable GI tumor undergoing FLOT regimen, do you have any data on whether the neoadjuvant chemo can be prolonged beyond 4 cycles in case patients are unable to tolerate the entire 4 cycles of adjuvant chemo? For example, increase the number of neoadjvant chemo to 5 or 6 cycles and then the adjuvant to 3 or 2 cycles with the same FLOT regimen?
In my experience, many patients did not tolerate neoadjuvant FLOT chemotherapy. Even though some patients could complete 4 cycles of FLOT, many could not have remaining 4 cycles due to surgery complications. I believe the FLOT study included 4 cycles of neoadjuvant and 4 cycles of adjuvant therapy although many patients could not complete full cycles. I do not believe there are any studies involving neoadjuvant chemo plus adjuvant chemotherapy with more cycles of neoadjuvant chemotherapy alone. In elderly or patients with comorbidities, FOLFOX or Xelox is better tolerated and patients can complete therapy. A large prospective Chinese study used Xelox.
@@stanleykim1924 Thank you very much Dr. Kim for your expertise. Do data suggest that the discontinuation rate of FLOT (both neoadjuvant and adjuvant combined) regimen is comparable to other regimen for GI cancer or does the rate seem to be higher/lower in FLOT?
@@stanleykim1924 If a patient is a candidate for a total gastrectomy, what might be some considerations before deciding to move forward with surgery? I understand that age and patient's status are some top considerations, but if a patient is elderly (i.e. 75yo) without significant medical history other than gastric cancer (and post neoadjuvant chemo), can you advise what other factors that a patient should consider when deciding next treatment plans when surgery is an option?
Love these Lectures, very helpful for trainees--Thank you Dr. Kim
Keynote 811 trial update ( ASCO GI Symposium Jan.2024):
The trial randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone.
Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).
On May 20, 2021, the Food and Drug Administration approved nivolumab for patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy.
Efficacy was evaluated in CHECKMATE-577 (link on the comment of 5/16/23 below), a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or GEJ cancers who had residual pathologic disease following concurrent chemoradiotherapy. Patients were randomized (2:1) to receive either nivolumab 240 mg or placebo every 2 weeks for 16 weeks followed by 480 mg of nivolumab or placebo every 4 weeks beginning at week 17 for up to one year of treatment.
CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients receiving nivolumab as compared to those on the placebo arm. The median DFS was 22.4 months (95% CI: 16.6, 34.0) versus 11 months (95% CI: 8.3, 14.3), respectively (HR 0.69; 95% CI: 0.56, 0.85; p=0.0003). The DFS benefit was observed regardless of tumor PD-L1 expression and histology.
In November 2023, the FDA approved pembrolizumab + chemo (FP or CAPOX) for advanced/metastatic HER2(-) gastric or GEJ adenocarcinoma.
When compared with chemo + placebo, improved OS (12.9 vs. 11.5 mon) and ORR 51 vs42%.
www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-her2-negative-gastric-or-gastroesophageal-junction
Locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery
More than one third of patients with locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery, findings from the Dutch SANO-trial suggest.
After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.
Overall, patients who underwent active surveillance had "noninferior overall survival at 2 years," of which study result was presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 on October 20.
Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene, Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death-ligand 1 (PD-L1) inhibitor.
Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator's choice of chemotherapy.
Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.
Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy.
The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.
Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
Pembrolizumab + chemotherapy improves 31-month survival over chemotherapy alone in HER2 (-) metastatic gastric or GEJ adenocarcinoma, regardless of PD-L1
(KEYNOTE-859)
www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00515-6/fulltext
At Median follow up of 31 months,
Median OS was 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo (HR 0.78, 95% CI 0.70-0.87; P < 0.0001). Median PFS was 6.9 mo vs 5.6 mo (HR 0.76, 95% CI 0.67-0.85; P < 0.0001). Results were generally consistent across subgroups, including those by PD-L1 CPS. ORR was 51.3% vs 42.0% (P = 0.00009). Median DOR was 8.0 mo vs 5.7 mo. Grade 3-5 treatment-related AEs occurred in 59.4% of 785 pts treated with pembro + chemo and 51.1% of 787 treated with placebo + chemo; 1.0% and 2.0%, respectively, died of treatment-related AEs.
However, this result is somewhat conflicting when compared with those of KEYNOTE-062:
The median overall survival of the patients who had pembrolizumab alone was compared with pembrolizumab + chemotherapy.
OS of the group w/ CPS 10 or higher: 17.4 vs 10.8 months. In KEYNOTE-859, median overall survival in the CPS 10 or higher group was 15.7 months. In other words, adding chemotherapy to the pembrolizumab in this group (CPS>10) may not be beneficial but more toxic.
Furthermore, the OS of the group w/CPS 1 or higher: pembrolizumab + chemo was not better than chemotherapy alone; and pembrolizumab alone was not inferior to chemotherapy.
In Keynote-811 trial where patients with metastatic gastric or GEJ cancer are treated with Pembrolizumab + Herceptin + chemotherapy (CAPOX or FOLFOX), duration of the treatment is up to 2 years or until disease progression or toxicity.
Super clear and helpful, really learn a lot, thank u soooo much!!! Plz keep updating 4 ever.
For HER2(-), PD-L1(-) gastric or GEJ cancer, chemotherapy was the treatment.
However, now, the standard therapy is combination of Keyruda and chemotherapy based on the KEYNOTE-859 trial.
The results from KEYNOTE-859 show the potential of KEYTRUDA plus chemotherapy to improve survival beyond chemotherapy alone for patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, regardless of PD-L1 expression
After neoadjuvant therapy and surgery for esophageal or GEJ adenocarcinoma, nevolymab increased DFS in patients with residual disease.
www.nejm.org/doi/full/10.1056/nejmoa2032125
HER-Vaxx which is a B-cell peptide targeted immunotherapy showed 41.5% survival benefit for patients with advanced gastric cancer when compared to the chemotherapy control group (phase 2, HERIZON study).
Thank you Dr. Kim for the great lecture! For patients with resectable GI tumor undergoing FLOT regimen, do you have any data on whether the neoadjuvant chemo can be prolonged beyond 4 cycles in case patients are unable to tolerate the entire 4 cycles of adjuvant chemo? For example, increase the number of neoadjvant chemo to 5 or 6 cycles and then the adjuvant to 3 or 2 cycles with the same FLOT regimen?
In my experience, many patients did not tolerate neoadjuvant FLOT chemotherapy. Even though some patients could complete 4 cycles of FLOT, many could not have remaining 4 cycles due to surgery complications. I believe the FLOT study included 4 cycles of neoadjuvant and 4 cycles of adjuvant therapy although many patients could not complete full cycles.
I do not believe there are any studies involving neoadjuvant chemo plus adjuvant chemotherapy with more cycles of neoadjuvant chemotherapy alone.
In elderly or patients with comorbidities, FOLFOX or Xelox is better tolerated and patients can complete therapy. A large prospective Chinese study used Xelox.
@@stanleykim1924 Thank you very much Dr. Kim for your expertise. Do data suggest that the discontinuation rate of FLOT (both neoadjuvant and adjuvant combined) regimen is comparable to other regimen for GI cancer or does the rate seem to be higher/lower in FLOT?
Much higher, for example, compared to FOLFOX. There is no direct comparison though.
@@stanleykim1924Thank you so much Dr. Kim!
@@stanleykim1924 If a patient is a candidate for a total gastrectomy, what might be some considerations before deciding to move forward with surgery? I understand that age and patient's status are some top considerations, but if a patient is elderly (i.e. 75yo) without significant medical history other than gastric cancer (and post neoadjuvant chemo), can you advise what other factors that a patient should consider when deciding next treatment plans when surgery is an option?
jamanetwork.com/journals/jamanetworkopen/fullarticle/2808569
Vitamin D supplement reduced P53+ GI cancer mortality. But not with p53- cancers.