The combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) has shown promising results in patients with platinum-refractory advanced B3-thymoma and thymic carcinoma, according to data from the phase 2 single-arm PECATI trial (NCT04710628) presented at the ESMO Congress 2024. The study demonstrated a 5-month progression-free survival (PFS) rate of almost 90% in this patient population without autoimmune disorders.
Jordi Remon, MD, PhD, from the Department of Cancer Medicine, Institut Gustave Roussy, stated, "It seems the outcome with this combination of pembrolizumab and lenvatinib, surpasses the activity of any of these agents as monotherapy. Therefore, we can conclude that the combination of pembrolizumab and lenvatinib could be considered a potential standard treatment for patients with B3-thymoma and thymic carcinoma and [advanced] disease at the time of platinum-refractory disease."
Efficacy Data
After a median follow-up of 10.6 months (range, 1.6-25.5), the 5-month PFS rate was 88.4% (95% CI, 73%-95%), meeting the trial’s primary end point. The median PFS was 14.9 months (95% CI, 10.6 to not evaluable), with a 12-month PFS rate of 56% (95% CI, 36%-72%).
Subgroup analyses indicated that the benefit from the combination was observed regardless of age, gender, and histologic subtype, although these findings were not statistically significant. Patients without liver metastases showed a statistically significant benefit compared to those with liver metastases (median PFS, 23.9 months [95% CI, 11.1-23.9] vs 10.9 months [95% CI, 2.8-14.9], respectively; HR, 0.3 [95% CI, 0.1-0.8]; P = .0151).
The objective response rate (ORR) was 23.3% (95% CI, 11.8%-38.6%), comprising 10 partial responses (23.3%), with 2 patients (4.7%) experiencing progressive disease, 22 patients (51.2%) achieving stable disease (SD) at 24 weeks or more, and 8 patients (18.6%) achieving SD at less than 24 weeks. The median duration of response was 8.2 months (95% CI, 6.1 to NE).
The 5- and 12-month overall survival (OS) rates were 95% (95% CI, 83%-99%) and 85% (95% CI, 67%-94%), respectively. The median OS was not reached at the almost 11-month follow-up.
Exploratory Analyses
Exploratory analyses of PFS by PD-L1 expression (n = 32; PD-L1<1% vs PD-L1 ≥1%) showed 5-month PFS rates of 94% (95% CI, 63%-99%) and 78% (95% CI, 46%-92%), respectively, with median PFS of 11 months (95% CI, 10-NE) and 10 months (95% CI, 5-NE). Remon suggested that PD-L1 expression may not be a strong predictive biomarker for selecting patients for this combination therapy.
However, a statistically significant benefit was observed among patients who did not have lenvatinib dose reduction compared to those with dose reduction within the first 8 weeks (median PFS, 23.9 months [95% CI, 14.9-NE] vs 8.4 months [95% CI, 7.1-NE], respectively; P < .001). "It seems that keeping the dose intensity of lenvatinib in the first 2 months after the treatment initiation might positively impact with this combination," Remon noted.
Safety Profile
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 20 patients (46.5%), with 16 (37.2%) experiencing grade 3 or higher treatment-related AEs (TRAEs). TRAEs leading to treatment discontinuation of any drug were seen in 11 patients (25.6%), although disease progression was the major cause of treatment discontinuation.
Severe AEs were reported in 7 patients (16.3%) and included pneumonitis, myocarditis/encephalitis, and cytolysis with pembrolizumab, and palmar-plantar syndrome, cardiac dysfunction, pulmonary abscess, and colitis with lenvatinib.
Remon emphasized the importance of close monitoring of patients due to these potential adverse events. The most common grade 3 or higher AEs were fatigue, diarrhea, hypertension, and palmar-plantar syndrome.
Study Design
The single-arm phase 2 trial included 43 patients with pre-treated, advanced B3-thymoma (16%) and thymic carcinoma (84%). Patients received 20 mg oral lenvatinib daily in combination with 200 mg pembrolizumab intravenously once every 3 weeks in 3-week cycles until disease progression, unacceptable toxicity, or a maximum treatment duration of 35 cycles.
Inclusion criteria comprised metastatic B3-thymoma and thymic carcinoma; at least 1 previous line of platinum-based chemotherapy; no autoimmune disorders; measurable disease; no intratumor cavitation, invasion of blood vessels, or previous bleeding; ECOG performance status of 0-1; and no previous treatment with sunitinib (Sutent).
The investigator-assessed 5-month PFS rate served as the primary end point. Secondary end points included ORR, disease control rate, OS, and safety.
The median age was 57 years (range, 33-80), and the majority of patients were male (58%). Most patients had received at least one prior line of therapy, with 17 (39%) and 3 (7%) undergoing 2 and 3 prior lines, respectively. More than half of patients (56%) had 3 or more metastatic sites, including 37% with liver metastases. The medium sum of target lesions was 86 mm (range, 11-204), suggesting a high tumor burden, and at least half (53%) of tumor samples were also PD-L1 negative.
