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Advanced Gastric Cancer

CE / CME

Cases and Challenges in the Optimal Treatment of Advanced Gastric Cancer

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: April 27, 2023

Expiration: April 26, 2024

Steven Maron
Steven Maron, MD
CME/CE Information

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Second- and Subsequent Line Treatment of Advanced GC

Second-line and later lines of treatment are chosen based on factors that include prior treatment history, molecular testing, and patient’s individual performance status, comorbidities, and preferences.4 

For the majority of patients, the recommended second-line approach is a combination of paclitaxel and the VEGFR2 inhibitor ramucirumab. Ramucirumab is administered intravenously every 2 weeks; in the recommended combination, paclitaxel is infused weekly.24 The recommendation for its use comes from the phase III RAINBOW trial, which evaluated addition of ramucirumab or placebo to paclitaxel for patients with progression within 4 months of completing first-line platinum/fluoropyrimidine chemotherapy with or without an anthracycline.25 On the primary endpoint of OS, addition of ramucirumab was associated with a 19% reduction in risk of death (HR: 0.81; 95% CI: 0.68-0.96; P = .017). Neutropenia was the most frequent grade ≥3 toxicity with added ramucirumab, reported in 41% of patients (vs 17% with placebo). Other grade ≥3 toxicities include leukopenia, hypertension, and fatigue.25 Any grade fatigue, neutropenia, peripheral edema, diarrhea, stomatitis, epistaxis, and hypertension were reported in 20% or more of patients receiving ramucirumab. 

Ramucirumab carries a warning that severe hemorrhage, GI perforation, or arterial thrombosis may occur, and require treatment discontinuation. Patients are at risk for impaired wound healing, new onset or worsening hypertension, and proteinuria while on treatment. Ramucirumab must be stopped at least 28 days prior to planned surgery. Hypertension and proteinuria are managed with treatment interruption or discontinuation, depending on severity.

 

Expert Insights From Dr Maron: Monitoring of ramucirumab therapy

 

Second-Line Therapy for HER2-Positive Advanced GC

Patients with HER2-positive mGC who have progressed after prior HER2-directed or other therapy derive optimal benefit from treatment with the antibody-drug conjugate (ADC trastuzumab deruxtecan (T-DXd.4 T-DXd consists of trastuzumab to target HER2 receptors on the tumor linked to cytotoxic deruxtecan, which is released into the tumor cell. It was evaluated vs standard chemotherapy in the phase 2 DESTINY-Gastric01 study in Japanese and South Korean patients who had progression on 2 or more prior therapies. Previous treatment with trastuzumab was allowed. The primary efficacy endpoint of the study was objective response rate, which was 51.3% with T-DXd vs 15.3% with chemotherapy.26,27 Median survival follow-up was 18.5 months. Treatment with T-DXd was associated with a 40% reduction in risk of death (HR: 0.60; 95% CI: 0.42-0.86; P = .01) in this open-label study. T-DXd also prolonged time to progression or death compared with chemotherapy (HR: 0.47; 95% CI: 0.31-0.71; P = .0003).27 T-DXd is FDA-approved for treatment of locally advanced or metastatic HER2-positive GC/GEJ adenocarcinoma after a prior trastuzumab-based regimen.28

Subsequently, an ongoing single-arm study in Western patients, DESTINY-Gastric02, reported that treatment with T-DXd was associated with a confirmed objective response rate of 41.8%, and median OS and PFS of 12.1 and 5.6 months, respectively. The 12-month OS rate was 50.6% in patients who had progressed on first-line trastuzumab-based therapy.29 Further, an exploratory analysis of patients with/without prior anti-PD-1 ICI therapy from DESTINY-Gastric01 found T-DXd was more effective than chemotherapy regardless of prior ICI exposure. This is an important point, as under current guidelines, an increasing number of patients will have been treated with an ICI as first-line therapy.30 Still being explored is the efficacy of T-DXd treatment for patients with so-called HER2-low GC, defined as IHC1-positive or IHC2-positive/ISH-negative. Results from a small number of patients enrolled in DESTINY-Gastric01 are promising, but more research is needed.31 

Of note, trastuzumab emtansine (T-DM1), an ADC effective in HER2-positive breast cancer, was no more effective than taxane therapy in second/subsequent line treatment of HER2-positive GC and did not improve OS in the phase III GATSBY study.32

 

Expert Insights From Dr Maron: Does tumor HER2 status need to be reconfirmed?

 

Which of the following was the most frequent grade 3 or 4 side effect of treatment with T-DXd in the DESTINY-Gastric01 trial?

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