Doubts About Apatinib for Gastric Cancer, Despite Approval

Pam Harrison

August 19, 2016

Three individual groups of physicians have raised doubts about the usefulness of apatinib, a new antiangiogenesis agent, in the treatment of advanced gastric cancer. They cite inconsistencies about how a pivotal trial assessing the drug was designed, and they question the validity of the conclusions reached by Chinese investigators.

In the meantime, apatinib, a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor 2 (VEGF-2), has been approved by the China Food and Drug Administration on the basis of the results of this trial, and the drug will now become commercially available in China, notes one of the authors.

The three groups write in separate letters to the editor published online August 15 in the Journal of Clinical Oncology. They express concerns over the pivotal phase 3 trial of apatinib that was published in the journal earlier this year (2016;34:1448-1454).

That study, led by Jin Li, MD, People's Liberation Army Cancer Center, Jiangsu, China, was conducted in 267 patients with advanced gastric cancer who had experienced disease progression after two or more lines of systemic therapy. The authors reported a modest overall survival advantage, at a median of 6.5 months for apatinib vs 4.7 months for placebo (hazard ratio, 0.709; P = .0149).

They concluded that apatinib "prolongs overall survival in heavily pretreated patients with gastric or gastroesophageal junction adenocarcinoma with moderate, reversible, and easily managed adverse events."

As such, the authors felt that apatinib could be considered a new treatment option for patients with advanced gastric cancer.

However, reaction to this conclusion and what some clinicians perceive to be design flaws in the study call into question the future of apatinib in the treatment of metastatic gastric cancer.

"In superiority trials, intention-to-treat (ITT) analyses that include all patients according to the allocated treatment are standard," writes Shen Zhang, MD, Fudan University, Shanghai, People's Republic of China, in his letter.

But as he points out, five patients in the apatinib group and one in the placebo group were not included in the ITT analyses, and their exclusion may have exaggerated the even modest survival benefit observed for apatinib.

More important, Dr Zhang questions just how tolerable apatinib is at the doses used in the trial.

"In the current study, Li et al concluded that a dose of 850 mg once per day is tolerable and acceptable," Dr Zhang observes. However, he points out that of the 40 patients who discontinued apatinib treatment, 22 (55%) stopped treatment as a result of toxicity, and dose reduction occurred in 21% patients who finished apatinib treatment.

In addition, he highlights the fact that "substantial" toxicities were reported with apatinib, 750 mg/day, in another trial, a phase 2 study investigating the drug for the treatment of breast cancer (Int J Cancer. 2014;135:1961-1969). In that trial, most of an admittedly small group of 25 patients required a dose reduction or delay during at least one treatment cycle.

"Almost all patients [in the trial] experienced grade ≥3 toxicity, and treatment-related death occurred in two patients," Dr Zhang adds.

"Therefore I question the conclusion of the phase III study of apatinib in patients with gastric cancer by Li et al," Dr Zhang concludes, and in an email to Medscape Medical News added that he is concerned about the toxicity of the drug.

Performance Status Discrepancies

In another letter questioning the design and results of the same study, Lorenzo Fornaro, MD, and colleagues from Azienda Ospedaliero-Universitaria Pisa, Italy, point out that there were more patients (27.3%) with a performance status (PS) of 0 in the active treatment group than in the placebo group (16.5%).

"The authors conclude that this difference does not formally reach statistical significance," they write.

"[But] even a seemingly mild deterioration in the general condition, that is, a PS of 1 according to the Eastern Cooperative Oncology Group scale, might impair outcomes in such a fragile patient scenario," they add.

The Italian group also concurs with Dr Zhang that apatinib resulted in "not negligible" rates of grade 3 to 4 toxicities, including an 8.5% incidence of hand-foot syndrome, high rates of generally low-grade proteinuria, and about a 6% incidence of grade 3 and 4 neutropenia.

"Is it really reasonable to conclude that apatinib 'has a favorable safety profile in comparison with other antiangiogenic agents'?" the Italian group asks.

Lastly, Dr Fornaro and coauthors highlight recent data reported for ramucirumab (Cyramza, Lilly) a large molecular and humanized IgG1 monoclonal antibody that largely targets the VEGF pathway.

The data from both the REGARD trial (Lancet. 2014;383:31-39), which used ramucirumab as monotherapy in patients with previously treated advanced gastric cancer, and the RAINBOW trial (Lancet Oncol. 2014;15:1224-1235), which used ramucirumab in combination with paclitaxel (RAINBOW), support the use of ramucirumab in much older patients than those treated in the Chinese study, Dr Fornaro and coauthors comment.

They point out that in the apatinib trial, the median age in the two study groups (58 years) is lower than that observed in routine practice. They also note that the Chinese investigators excluded elderly patients (age > 70 years) and that the number of patients aged 65 to 70 years was limited (37 patients).

The data from the REGARD trial also show that ramucirumab appears to be associated with an improvement in quality of life, they add.

"With an arguably increasing number of patients receiving ramucirumab in the second-line setting, it is difficult to anticipate the potential impact of apatinib in routine clinical practice," Dr Fornaro and colleagues write.

In addition, "as these agents share the same target along the pathways that regulate tumor angiogenesis, the efficacy of apatinib in overcoming resistance to ramucirumab is unclear." They consider apatinib to be a "doubtful step forward."

In an editorial that accompanied the apatinib study publication, David H. Ilson, MD, PhD, from the Memorial Sloan Kettering Cancer Center, New York, New York, noted that the modest improvement in overall survival reported for apatinib are "consistent" with those reported previously with ramucirumab, and these "small survival improvements across these trials add to evidence that the VEGF pathway is a viable therapeutic target."

But while these small improvements in survival are statistically significant, are they clinically meaningful? Dr Ilson also asks about the relative cost vs the benefit.

Most Participants Male

Replying to these concerns, senior author of the Chinese study, Shukui Qin, MD, People's Liberation Army Cancer Center, Nanjing, People's Republic of China, counters that 75% of participants in their study were male and that men may well be able to tolerate higher doses of apatinib than women.

Furthermore, the average dose of apatinib in the study was around 750 mg/day and not 850 mg/day, as was the stated target dose.

Dr Qin also notes that grade 3 to 4 proteinuria rates were actually lower in their own study than they were in the REGARD study with ramucirumab.

And he defended the median age of 58 years in their trial because in China, people aged 45 to 64 years have the highest rates of gastric cancer in the country, thus justifying the exclusion of more elderly patients from their study.

"Ramucirumab has not yet been approved for use in China," Dr Qin writes. "So we look forward to proceeding with head-to-head studies of the two drugs in the future."

The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online August 15, 2016. Zhang letter Fornaro letter Lee letter Qin letter

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