Targeted Therapy Gaining Ground in the Second-line Treatment of Gastric Cancer 


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In gastric cancer, the concept of targeted therapy assumed clinical significance when the addition of trastuzumab (Herceptin) to chemotherapy improved survival by almost 3 months in the ToGA trial.1 Another anti-HER2 agent, lapatinib (Tykerb), now looks promising, as does an agent targeting the vascular endothelial growth factor (VEGF) pathway, ramucirumab. Data presented at the 2013 Gastrointestinal Cancers Symposium validated the concept of using targeted agents in a disease that, until fairly recently, depended on cytotoxic chemotherapy to only marginally improve outcomes, said Neal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, the ASCO representative on the symposium’s news planning committee. 

“Five years ago all we had in stomach cancer were toxic drugs that we piled on top of each other with only modest improvements, and a lot of toxicity. Now, we see drugs adding benefit without many side effects. This is further opening the door into targeting pathways, rather than using a blind shot,” Dr. Meropol told The ASCO Post.

Ramucirumab Improves Survival

In a study that drew a large crowd at the poster presentation, an international team of investigators reported an improvement in overall survival with the anti-VEGF monoclonal antibody ramucirumab in metastatic gastric cancer progressing after first-line treatment.2 Patients who received ramucirumab as a single agent had a median overall survival of 5.2 months, compared to 3.8 months for placebo, translating into a 28% reduced risk of dying (P = .0473). 

Ramucirumab conferred a significant 52% reduction in the risk of progression. Median progression-free survival was 2.1 months with ramucirumab vs 1.3 months with placebo, and 12-week progression-free survival was 40% vs 16%, respectively.

“The findings suggest that ramucirumab is a potential new second-line treatment in this patient population,” said Charles Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, Boston.

VEGF and VEGF receptor 2–mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab is a fully human IgG1 monoclonal antibody targeting VEGF receptor 2.

The placebo-controlled, double-blind, randomized phase III international trial evaluated ramucirumab  (8 mg/kg IV) vs best supportive care in 355 patients with metastatic gastric or gastroesophageal junction adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine-containing combination therapy. The primary endpoint was overall survival.

“The preliminary assessment found that overall survival and progression-free survival favored ramucirumab within each of the individual strata of the prespecified stratification factors. These included weight loss, geographic region, and location of the primary tumor,” Dr. Fuchs said.

The overall response rate was low for both—3.3% and 2.6%, respectively—but the disease control rate was doubled with ramucirumab, 48.9% vs 23.1% (P < .0001).

The drug was well tolerated, with grade 3/4 adverse events occurring in no more than 8% of patients on ramucirumab. Treatment-emergent deaths were similar between the arms, 10.6% with ramucirumab and 13.0% with placebo. 

Discussing the findings, Dr. Fuchs discussed how ramucirumab might be used, hypothetically. “One could take this in several different directions. We could apply it as a single agent or combine it with chemotherapy in a relatively unselected population. We could also think in terms of biology, and identify subgroups in whom we would give it in combination with another biologic, perhaps another modulator of the VEGF pathway with which it would be synergistic—and give no cytotoxics at all. This would minimize toxicity and hopefully achieve the same efficacy,” he suggested. 

Second-line Lapatinib plus Paclitaxel

In another presentation of interest, Yung-Jue Bang, MD, Director of the Clinical Trials Center at Seoul National University Hospital in South Korea, presented the results of the TyTAN trial, which enrolled 261 HER2-amplified Asian patients with advanced gastric cancer who progressed after first-line treatment.3 They were randomly assigned to receive paclitaxel (80 mg/m2 day 1, 8,15 every 28 days) alone, or paclitaxel plus lapatinib at 1,500 mg/d.

The combination led to a nonsignificant 2.1-month improvement in overall survival. Among the prespecified subgroup of patients with strong HER2 positivity, however, statistically significant benefits were shown for the combination in both overall survival and progression-free survival, Dr. Bang reported.

Median overall survival was 11.0 months with lapatinib/paclitaxel vs 8.9 months with paclitaxel alone (HR = 0.84; P = .208). Progression-free survival was 5.4 vs 4.4 months, respectively (HR = 0.85; P = .24).

In patients with HER2 expression by immunohistochemistry (IHC) of IHC 3+, median overall survival was 14.0 months, vs 7.6 months with paclitaxel alone (HR = 0.59; P = .0176), and progression-free survival was 5.6 months vs 4.2 months, respectively (HR = 0.54; P = .0101).

“One of the major reasons for the negative outcome may be the unexpectedly high proportion of IHC 0/1+ patients in the study—35%,” Dr. Bang suggested. “Among the subgroup in the prospectively defined  IHC 3+ subgroup, however, a significant benefit was observed in both overall and progression-free survival.” 

The incidence of diarrhea was 77% with the combination and 22% with paclitaxel, and was grade 3/4 in 18% and 2%, respectively. ■

Disclosure: Dr. Fuchs has served in a consultant or advisory role for Amgen, Bayer, Bristol-Myers Squibb, Genentech, Infinity Pharmaceuticals, Metamark Genetics, Momenta Pharmaceuticals, Pfizer, Roche, and Sanofi. Dr. Bang has served in a consultant or advisory role for GlaxoSmithKline, Roche, Pfizer, Novartis, Sanofi-Aventis, AstraZeneca, Merck, Bristol-Myers Squibb, Lilly, Bayer, Genentech, Amgen and has received honoraria from GlaxoSmithKline, Roche, Novartis, Pfizer, and Lilly.

References

1. Bang Y-J, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2012.

2. Fuchs CS, Tomasek J, Cho JY, et al: REGARD: A phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy. 2013 Gastrointestinal Cancers Symposium. Abstract LBA5. Presented January 24, 2013.

3. Bang Y-J, Ruihua X, Taroh S, et al: A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian population: TyTAN study. 2013 Gastrointestinal Cancers Symposium. Abstract 11. Presented January 24, 2013.


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