Objective response rates and progression-free survival rates best single-agent pembrolizumab

The combination of immunotherapy plus a multikinase inhibitor has shown impressive anti-tumor activity in advanced gastric cancer and the doublet was reasonably well tolerated, a single-arm, phase II trial has indicated.

In a small study involving 29 patients, treatment with pembrolizumab, an anti-PD-1 antibody, plus lenvatinib, a multikinase inhibitor of vascular epithelial growth factor (VEGF) receptors and other receptor tyrosine kinases, led to an objective response rate of 69% (95% CI, 49-85%) and a median progression-free survival (PFS) of 7.1 months (95% CI, 5.4-13.7 months) in patients with advanced gastric cancer, Akihito Kawazoe, MD, National Cancer Center Hospital East, Chiba, Japan and colleagues reported in the Lancet Oncology.

After excluding 2 patients who were MMR-deficient, an objective response of 70% (95% CI, 50-86%) was seen in 27 patients with MMR-proficient tumors, researchers added.

Grade 3 treatment-related adverse events (AEs) occurred in 48% of the group, but there were no grade 4 treatment-related AEs, and no treatment-related AEs caused patients to withdraw from the study, although 7% discontinued lenvatinib because of AEs.

“To our knowledge, this study is the first to evaluate the combined activity of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting,” Kawazoe and colleagues observed.

“This combination showed a higher objective response rate than that of single drugs in previous studies…and further investigation of lenvatinib plus pembrolizumab in this disease setting is warranted,” they said.

On enrollment, patients had metastatic or recurrent adenocarcinoma of the stomach or gastro-esophageal junction and measurable lesions specified in the Response Evaluation Criteria in Solid Tumors (RECIST: version 1.1).

Treatment consisted of oral lenvatinib, 20 mg, once a day, and 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity or withdrawal of consent.

“The primary endpoint was investigator-assessed objective response rate according to RECIST,” the authors noted.

The median number of treatment cycles was 10 (95% CI, 7-18 cycles) and at data cutoff some 5 months after enrollment, 28% of patients were still receiving treatment, the rest having discontinued the protocol because of disease progression.

At a median follow-up of 12.6 months (Interquartile Range (IQR): 10.5-14.3 months), “[a] similar objective response rate was observed in patients receiving the study treatment as first-line and in those receiving it as second-line,” investigators pointed out.

Moreover, of those patients who achieved an objective response to treatment, responses were still ongoing in 45% of patients at the same data cutoff point.

In the overall group, 3% of patients achieved a complete response (CR); 66% achieved a partial response (PR) and disease stabilized in 31%, investigators reported.

Disease was also controlled in all 29 patients (100%, 95% CI, 88-100%) while all but one patient in whom disease stabilized had evidence of initial tumor shrinkage compared with baseline values.

Again, at the data cutoff point, the median overall survival (OS) had not been reached (95% CI, 11.8 months to not reached), the authors observed.

PD-L1 combined positive score (CPS) was evaluated in all patients while tumor mutational burden (TMB) could be assessed in 21 patients.

In what was a prespecified analysis, objective responses were observed in 84% of patients (95% CI, 60-97%) with a PD-L1 CPS of at least 1 compared to only about half that at 40% of patients (95% CI, 12-74%) with a CPS of less than 1.

Moreover, in the subgroup of five patients with a CPS of 10 or higher, all five (100%, 95% CI, 48-100%) achieved an objective response, researchers added.

Some 11 patients had a high TMB and in this subgroup of patients, 82% (95% CI, 48-98%) had an objective response compared to 60% of another 10 patients who had a low TMB.

Progression-free survival rates also favored those with a CPS of at least 1 while median PFS rates were equivalent between patients with a high and a low TMB.

  • Median PFS: 9.1 months (95% CI, 5.6 months to not reached) in patients with a CPS of at least 1.
  • Median PFS: 5.9 months (95% CI, 3.2 months to not reached) in patients with a CPS of less than 1.
  • Median PFS: 9.8 months (95% CI, 4.0 months to not reached) in patients with a high TMB.
  • Median PFS: 9.5 months (95% CI, 2.8 months to not reached) in patients with a low TMB.

The most common grade 3 treatment-related AE was hypertension in 38% of patients followed by proteinuria in 17% and a drop in platelet counts in 7%—”most of which were reversible by a reduction [in the dose] of lenvatinib, dose interruptions or administration of antihypertensive drugs,” the authors observed.

Indeed, all but one patient required a dose interruption with lenvatinib because of treatment-related AEs and all patients required at least one dose reduction for the same reason.

Commenting on study results, Stefano Cascinu, MD, San Raffaele Hospital, Milan, Italy, pointed out that in contrast to these promising results, both KEYNOTE-062 in the first-line setting and KEYNOTE-061 in the second-line setting showed that treatment with pembrolizumab alone led to a response rate of only 16% in patients with advanced gastric cancer, both groups of patients having a PD-L1 CPS of at least 1.

In KEYNOTE-062, the median PFS rate was only 2.0 months (95% CI, 1.5-2.8 months).

The current combination thus presents “new opportunities” for the treatment of advanced gastric cancer, as Cascinu suggested.

On a cautionary note, however, the editorialist pointed out that a potential weakness of the study is a lack of preclinical data in gastric cancer and the fact that patients with gastric cancer were not included in an earlier phase I trial evaluating the same combination of lenvatinib and pembrolizumab.

Moreover, “[a] crucial point, as acknowledged by Kawazoe and colleagues themselves, is that these findings need to be confirmed in Europe and North America,” he emphasized.

This is because a subgroup analysis of the KEYNOTE-062 trial showed that pembrolizumab was more effective in Asian patients than in the non-Asian population.

Cascinu also pointed out that objective responses, while the primary endpoint of the study, were not reviewed centrally.

“Since it is not uncommon that investigators overestimate responses, this high proportion of responses should be further confirmed before moving toward a randomized phase III trial,” Cascinu suggested.

  1. The combination of immunotherapy with pembrolizumab plus the multikinase inhibitor, lenvatinib, demonstrated impressive anti-tumor activity in patients with advanced gastric cancer.

  2. Objective response rates were significantly higher and progression-free survival rates significantly longer when the combination strategy was used compared to single-agent pembrolizumab in metastatic or recurrent adenocarcinoma of the stomach or gastro-esophageal junction.

Pam Harrison, Contributing Writer, BreakingMED™

Kawazoe reported receiving grants and personal fees from Taiho Pharmaceutical and Ono Pharmaceutical as well as grants from Sumitomo Dainippon Pharma and Merck Sharp & Dohme.

Cascinu had no conflicts of interest to declare.

Cat ID: 23

Topic ID: 78,23,730,16,23,935,192