Lenvatinib/Pembrolizumab Combo Shows Promise in Thymic Epithelial Tumors

Jordi Remon, MD, PhD

Treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) demonstrated a 5-month progression-free survival (PFS) rate of almost 90% in patients with platinum refractory advanced B3-thymoma and thymic carcinoma without autoimmune disorders, according to data from the phase 2 single-arm PECATI trial (NCT04710628) presented at ESMO Congress 2024.¹

“It seems the outcome with this combination of pembrolizumab and lenvatinib, surpasses the activity of any of these agents as monotherapy,” Jordi Remon, MD, PhD, Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, said during a presentation at the congress. “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.”

After a median follow-up of 10.6 months (range, 1.6-25.5) following data cutoff, the 5-month PFS rate was 88.4% (95% CI, 73%-95%), meeting the trial’s primary end point. Median PFS was 14.9 months (95 CI, 10.6 to not evaluable [NE]), with a 12-month PFS rate of 56% (95% CI, 36%-72%).

According to subgroup analyses, benefit from the combination of lenvatinib plus pembrolizumab was seen regardless of stratification by age, gender, and histologic subtype; however, they were not statistically significant. Among patients with no liver metastases, vs those with, there was a statistically significant benefit from the combination regimen (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).

Objective response rate (ORR) was 23.3% (95% CI, 11.8%-38.6%), including no complete responses, 10 partial responses (23.3%), 2 patients (4.7%) with progressive disease, 22 patients (51.2%) with stable disease (SD) at 24 weeks or more, and 8 patients (18.6%) with SD at less than 24 weeks. 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. Median OS was not reached at the almost 11-month follow-up.

Investigators conducted exploratory analyses of PFS by PD-L1 expression (n = 32; PD-L1<1% vs PD-L1 ≥1%) and lenvatinib dose intensity (without dose reduction [56%] vs with dose reduction within the first 8 weeks [44%]).

Microscopic photorealistic image of thyroid cancer cells - Generated with Google Gemini AI

Among patients with PD-L1 <1%, the 5-month PFS rate was 94% (95% CI, 63%-99%), compared with 78% (95% CI, 46%-92%) in the PD-L1 ≥1% group, with median PFS of 11 months (95% CI, 10-NE) and 10 months (95% CI. 5-NE), respectively. “[This does] not strongly support that…PD-L1 expression should be considered a potential predictive biomarker for selecting the patients that may obtain the maximum benefit of this combination,” Remon said.

However, he noted subgroup analysis demonstrated a statistically significant benefit from the combination among those who did not have lenvatinib dose reduction, vs 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 said.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 20 patients (46.5%), while 16 (37.2%) experienced grade 3 or higher treatment-related AEs (TRAEs). Further, TRAEs leading to treatment discontinuation of any drug was seen in 11 patients (25.6%); however, the major cause of treatment discontinuation in the trial was disease progression, according to Remon.

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.

“If we're going to use this strategy in our daily clinical practice, it's really important to perform a close monitoring of all of these patients,” Remon explained.

The most common grade 3 or higher AEs were fatigue, diarrhea, hypertension, and palmar-plantar syndrome.

Thymic epithelial tumors are rare and heterogenous, leading to a poor prognosis and high incidence of autoimmune disorders, particularly myasthenia gravis, Remon noted. Further, current treatment options for platinum-refractory disease are limited, with no specific standard second-line treatment available.

“In this scenario, both the immune checkpoint blockers and also the drugs with antiangiogenic properties have reported a clinical meaningful activity, either as a monotherapy, but also in combination,” he added.

Therefore, investigators aimed to assess the efficacy and safety of lenvatinib plus pembrolizumab in 43 patients with pre-treated, advanced B3-thymoma (16%) and thymic carcinoma (84%).

In the single-arm phase 2 trial, patients received 20 mg oral lenvatinib daily in combination with 200 mg pembrolizumab intravenously once ever 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).

Investigator-assessed 5-month PFS rate served as the primary end point. Secondary end points included ORR, disease control rate, OS, and safety.

Median age was 57 years (range, 33-80), and the majority of patients were male (58%). The majority of patients received at least 1 prior line of therapy, with 17 (39%) and 3 (7%) undergoing 2 and 3 prior lines, respectively. Further, 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, Remon said, adding that at least half (53%) of tumor samples were also PD-L1 negative.

REFERENCE:

Remon J, Bironzo P, Girard N, et al. Lenvatinib plus pembrolizumab in pretreated advanced B3-thymoma and thymic carcinoma: PECATI, single arm phase II clinical trial. Presented at: ESMO Congress 2024; September 12-16, 2024; Barcelona, Spain. Abstract LBA83.