Abstract
Background
Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs.
Patients and methods
A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment.
Results
Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment.
Conclusions
The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.
Key words: pembrolizumab, lenvatinib, neuroendocrine tumor, immunotherapy
Highlights
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The combination of antiangiogenic and CPIs has been shown to be synergistic in other cancers, evaluated in NETs.
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Twenty patients were enrolled and treated on trial, with a 10% ORR and median PFS of 8 months.
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The toxicity profile was within expectations for the drug combination.
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The combination of pembrolizumab and lenvatinib did not show sufficient response in NETs to warrant continued enrollment.
Introduction
Well-differentiated neuroendocrine tumors (NETs) are characterized by a high level of vascularization as well as overexpression of the vascular endothelial growth factor receptor (VEGFR).1,2 Receptor tyrosine kinase inhibitors (RTKIs) targeting VEGFR have demonstrated activity in advanced NETs. Sunitinib, an inhibitor of VEGFR subtypes 1-3 and platelet-derived growth factor receptor (PDGFR), demonstrated significant improvement in progression-free survival (PFS) compared to placebo among patients with pancreatic NETs.3 Parallel phase III studies of surufatinib, an inhibitor of VEGFR 1-3 as well as fibroblast growth factor receptor (FGFR-1), were conducted in China, enrolling patients with pancreatic and gastrointestinal (GI)/thoracic NETs.4,5 Both trials demonstrated statistically significant improvement in PFS versus placebo. Other RTKIs, such as pazopanib, axitinib, and cabozantinib, have also shown evidence of activity in advanced pancreatic as well as GI and thoracic NETs, although a phase III trial of axitinib versus placebo in GI/thoracic NETs fell short of statistical significance.6, 7, 8, 9 Among antiangiogenic tyrosine kinase inhibitors (TKIs), lenvatinib stands out as demonstrating particularly high objective radiographic response rates (ORRs). Lenvatinib is an inhibitor of VEGFR 1-3, FGFR 1-4, PDGFR, and c-KIT. The single-arm phase II TALENT trial evaluated 111 patients in two cohorts: progressive pancreatic NETs (55 patients) or GI NETs (56 patients).10 The ORR was 30%: 44% in the pancreatic NET cohort and 16% in the GI NET cohort. Median PFS was 15.7 months.
In addition to inhibiting angiogenesis, VEGF inhibitors may play a role in mediating antitumoral immune response.11 VEGF induces the mobilization of regulatory T cells (Tregs) which can secrete immunosuppressive cytokines.12 VEGFR inhibitors have been shown to stimulate dendritic cell antigen presentation, T-cell activation, and migration to tumor sites, and also to inhibit generation of Tregs along with immunosuppressive cytokines such as interleukin-10 and transforming growth factor -β. Thus, VEGFR TKIs can potentially reverse the immunosuppressive effects of the tumor microenvironment.
Preclinical evidence of immunomodulation has provided the basis for investigating the combination of VEGFR inhibitors with immune checkpoint inhibitors (CPIs). Drugs targeting the programmed cell death protein (PD-1) receptor or its ligand (PD-L1) have shown minimal activity in well-differentiated NETs with ORRs generally below 5%.13, 14, 15, 16, 17 The very low median tumor mutation burden (TMB) and, consequently, low neoantigen presentation likely contribute to low response rates against well-differentiated NETs. Strategies to enhance immune response are therefore necessary, and combinations of CPIs with RTKIs are of particular interest.
Clinical indications of synergy between immune CPIs and RTKIs exist in other cancer types.18, 19, 20, 21 Keynote 146, a phase Ib/II study, evaluated pembrolizumab plus lenvatinib in certain solid tumors, establishing a recommended dose of lenvatinib 20 mg orally daily and pembrolizumab 200 mg intravenously (i.v.) every 3 weeks.22 Based on particularly promising response rates in endometrial cancer patients [64% ORR in microsatellite instability (MSI)-high patients and 36% in microsatellite-stable patients], the phase III Keynote 775 study was launched to investigate lenvatinib plus pembrolizumab versus investigator-choice chemotherapy in patients with advanced endometrial cancer beyond first-line therapy.23 A total of 827 patients [697 with mismatch repair-proficient (pMMR) and 130 with mismatch repair-deficient disease] were randomized. Results showed a statistically significant improvement in overall survival (OS) with pembrolizumab/lenvatinib both in the overall population (hazard ratio 0.62) and the pMMR population (hazard ratio 0.68), thus establishing the efficacy of this treatment combination.
To assess whether evidence of synergy between RTKI and VEGFR inhibitor exists in well-differentiated NETs, we designed a phase II study evaluating the combination of pembrolizumab and lenvatinib. The primary endpoint selected was ORR given the difficulty of interpreting PFS outcomes in a single-arm trial. Due to the high documented ORR of 40% with lenvatinib monotherapy in the GETNE study, pancreatic NETs were excluded from our trial, and the study population was restricted to well-differentiated NETs originating in the GI tract and thorax (lungs and thymus).
Patients and methods
Patient selection and eligibility
This study was an open-label, single-arm, phase II study of pembrolizumab and lenvatinib in patients with well-differentiated NETs. The protocol [NCT03290079; IND number (IND-Exempt): IND-135156] was approved by the Advara institutional review board (Pro00023052) and was conducted in accordance with Good Clinical Practice principles. Written informed consent was obtained from all participants before any study-related procedures.
Subjects were eligible if they were adults (age ≥18 years) with metastatic well-differentiated (grade 1-3 per World Health Organization 2020) NETs of primary lung, thymic, gastric, small bowel, colorectal, or unknown primary origin.24,25 Poorly differentiated neuroendocrine carcinomas and pancreatic primaries were not eligible for enrollment. Patient must have had evidence of radiographic disease progression per investigator assessment within 8 months of consent and had received a minimum of two prior lines of systemic therapy. There was no limit to number of prior lines of treatment, and concurrent therapy with somatostatin analogs was permitted in patients with hormonal syndromes. Other key eligibility criteria were measurable disease per RECIST 1.1, Eastern Cooperative Oncology Group (ECOG) performance status of ≤1, absolute neutrophil count ≥1500 cells/μl, platelets ≥100 000 cells/μl, hemoglobin ≥9 g/dl, urine protein <30 mg/dl on urinalysis or ≤1 g/24 h on 24-h urine protein, total bilirubin ≤1.5× upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase ≤2.5× ULN or ≤5× ULN for patients with liver metastases, albumin ≥2.5 mg/dl, and international normalized ratio (INR)/prothrombin time ≤1.5× ULN. Key exclusion criteria included a history of immunodeficiency or concurrent systemic steroid/immunosuppressive therapy use, prior therapy with any TKIs or anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, uncontrolled hypertension defined as blood pressure of >150/90 despite optimal medical management, history of thromboembolic events within 6 months of enrollment and/or use of anticoagulants requiring INR monitoring, and baseline prolongation of QTcF ≥ 480 ms.
Treatment and evaluation
Cycles were defined as 21 days (±3 days) for up to 35 cycles. Pembrolizumab was administered i.v. at a dose of 200 mg every 3 weeks and lenvatinib was orally administered at a dose of 20 mg once daily. Dose reductions of the lenvatinib were allowed in a stepwise fashion: 14 mg, 10 mg, and 8 mg. No dose reductions were permitted of the pembrolizumab; however, patients were eligible to continue monotherapy of either drug should they become intolerant to or experience unacceptable adverse events (AEs) requiring the discontinuation of one. Dose modifications for immune-related AE and lenvatinib-related AEs were outlined in detail in the protocol.
Baseline radiographic assessments of tumor burden (multiphasic computed tomography or magnetic resonance imaging scans) were completed within 28 days of initiation of study treatment and repeated every 9 weeks from start of treatment for the first year, then every 12 weeks for the second year. RECIST version 1.1 was used for evaluation of primary endpoint of response rate. Optional archival tissue was collected and sent to QualTek for correlative analysis of PD-L1 tumor expression, TMB, and microsatellite instability status.
Sample size calculation
The primary endpoint of the trial was objective radiographic response rate (ORR). Secondary endpoints included PFS, duration of response per RECIST 1.1, OS, as well as safety and tolerability of the combination in this patient population, assessed per version 5.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. PFS was defined as the time from initial treatment to the first documented disease progression according to RECIST 1.1, or death due to any cause, whichever occurs first. OS was defined as the time from initial treatment until death from any reason. Patients without an event were censored at last date seen. Exploratory objectives were to correlate radiographic response with PD-L1 tumor expression and presence of tumor-infiltrating lymphocytes (TILs).
The study was a standard phase II study, utilizing a Simon two-stage design. The sample size calculation was based on the assumption that a true response of >38% would generate interest in a larger randomized study, where a response rate of <18% would not yield any further interest in this drug combination for this disease. Based on this, 35 patients were needed to test the hypothesis that the true response is 38% versus 18% with a power of 90% and type 1 error rate of 8%. Patients were to be accrued to the trial according to Simon’s two-stage minimax design and 20 patients would be enrolled into stage 1. If four or more responses were observed, then another 15 patients were to be enrolled into stage 2. At the completion of the study, 10 or more responders out of 35 were needed to consider the statistical significance of 8% met.
Statistical analysis
The Kaplan–Meier method was used to estimate all time-to-event functions. PFS was defined as the time from start of treatment until progression of disease or death due to any cause. OS was defined as the time from start of treatment until death due to any cause, with patients censored at the date of last follow-up if still living. PFS estimates were to be calculated at the 3-, 6-, and 12-month timepoints, and OS would be noted at the median and 12-month timepoints. Exact 95% confidence intervals (CIs) were calculated for each proportion of interest. Overall safety would be assessed by identifying the highest toxicity grade for each patient and further evaluated in select toxicities. Statistical analysis was carried out using IBM SPSS v26.
Results
Patient population
A total of 20 patients were enrolled between April 2021 and January 2022: nine primary small intestinal, five pulmonary, two thymic, two unknown primary, one cecal, one presacral. Median age of the patient population at the time of enrollment was 63 years (range: 33-81 years): 12 males and 8 females. All patients had an ECOG performance status of 0-1 at enrollment and had received a median of three prior lines of systemic therapy. Nine patients received concurrent somatostatin analog during the trial. Table 1 summarizes the demographic characteristics of the study population.
Table 1.
Patient demographics
| N | % | |
|---|---|---|
| Gender | ||
| MALE | 12 | 60% |
| FEMALE | 8 | 40% |
| AGE AT ENROLLMENT, YEARS | ||
| 30-45 | 3 | 15% |
| 46-60 | 6 | 30% |
| 61-75 | 8 | 40% |
| 76+ | 3 | 15% |
| PRIOR LINES OF SYSTEMIC THERAPY | ||
| 2 | 7 | 35% |
| 3 | 9 | 45% |
| 4+ | 4 | 20% |
| PRIMARY SITE OF DISEASE | ||
| SMALL INTESTINE | 9 | 45% |
| LUNG | 5 | 25% |
| THYMUS | 2 | 10% |
| UNKNOWN PRIMARY | 2 | 10% |
| CECUM | 1 | 5% |
| PRESACRUM | 1 | 5% |
| KI-67% | ||
| ≤2% | 3 | 15% |
| 3%-20% | 11 | 55% |
| >20% | 6 | 30% |
Duration of therapy
All patients were evaluable for toxicity analysis and received at least one cycle of therapy. Patients received an average of 11 cycles each of pembrolizumab and lenvatinib. Reasons for discontinuation of therapy included radiographic disease progression (10 patients), clinical progression (3 patients), toxicity (3 patients), death on study (2 patients), and other complicating disease, unrelated to primary disease or drug (1 patient). One patient remains on study. Toxicities leading to treatment discontinuation included grade 2 fatigue and grade 3 hypertension (1 patient) and grade 3 AST elevation and grade 2 rash (1 patient), and grade 3 brittle, insulin-dependent diabetes (1 patient). Table 2 represents all AEs possibly, probably, or definitely related to study drug and occurring in 2 or more patients. All data are available upon request.
Table 2.
Treatment-related adverse events per CTCAE v5.0
| G1 (n, %) | G2 (n, %) | G3 (n, %) | ||||
|---|---|---|---|---|---|---|
| HYPERTENSION | 1 | 5% | 6 | 30% | 10 | 50.0% |
| FATIGUE | 4 | 20% | 5 | 25% | 3 | 15.0% |
| DIARRHEA | 6 | 30% | 3 | 15% | 0 | 0.0% |
| HEADACHE | 4 | 20% | 4 | 20% | 1 | 5.0% |
| WEIGHT LOSS | 4 | 20% | 4 | 20% | 0 | 0.0% |
| PROTEINURIA | 5 | 25% | 3 | 15% | 0 | 0.0% |
| PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME | 2 | 10% | 4 | 20% | 0 | 0.0% |
| ABDOMINAL PAIN | 2 | 10% | 4 | 20% | 1 | 5.0% |
| HYPOTHYROIDISM | 0 | 0% | 6 | 30% | 0 | 0.0% |
| SINUS TACHYCARDIA | 1 | 5% | 5 | 25% | 0 | 0.0% |
| BACK PAIN | 2 | 10% | 2 | 10% | 1 | 5.0% |
| ARTHRALGIA | 2 | 10% | 3 | 15% | 0 | 0.0% |
| RASH MACULOPAPULAR | 3 | 15% | 1 | 5% | 1 | 5.0% |
| DYSPNEA | 1 | 5% | 3 | 15% | 0 | 0.0% |
| MUCOSITIS ORAL | 3 | 15% | 1 | 5% | 0 | 0.0% |
| VOMITING | 2 | 10% | 2 | 10% | 0 | 0.0% |
| HYPOTENSION | 1 | 5% | 1 | 5% | 1 | 5.0% |
| COUGH | 2 | 10% | 1 | 5% | 0 | 0.0% |
| DIZZINESS | 2 | 10% | 1 | 5% | 0 | 0.0% |
| DYSGEUSIA | 0 | 0% | 3 | 15% | 0 | 0.0% |
| ANOREXIA | 0 | 0% | 3 | 15% | 0 | 0.0% |
| ADRENAL INSUFFICIENCY | 0 | 0% | 0 | 0% | 2 | 10.0% |
| CHILLS | 1 | 5% | 1 | 5% | 0 | 0.0% |
| CONFUSION | 1 | 5% | 1 | 5% | 0 | 0.0% |
| CONSTIPATION | 1 | 5% | 1 | 5% | 0 | 0.0% |
| EDEMA LIMBS | 1 | 5% | 1 | 5% | 0 | 0.0% |
| EPISTAXIS | 2 | 10% | 0 | 0% | 0 | 0.0% |
| FALL | 1 | 5% | 1 | 5% | 0 | 0.0% |
| FEVER | 1 | 5% | 1 | 5% | 0 | 0.0% |
| GENERALIZED MUSCLE WEAKNESS | 0 | 0% | 2 | 10% | 0 | 0.0% |
| HEMATURIA | 1 | 5% | 1 | 5% | 0 | 0.0% |
| HYPERTHYROIDISM | 1 | 5% | 1 | 5% | 0 | 0.0% |
| MYALGIA | 2 | 10% | 0 | 0% | 0 | 0.0% |
| NAUSEA | 1 | 5% | 1 | 5% | 0 | 0.0% |
| PAIN (LOWER BACK PAIN AND RIGHT iliac CREST) | 0 | 0% | 1 | 5% | 1 | 5.0% |
CTCAE, common terminology criteria for adverse events.
Radiographic response
Eighteen patients were assessable for radiographic response. Two patients discontinued treatment on study before restaging (one after cycle 1 and the other after cycle 2) and were not re-evaluated with scans. There were two objective responders per RECIST 1.1 (ORR: 10%; 95% CI 0.03% to 0.30%), one patient with a grade 2 small bowel NET and one with an atypical lung NET. When best response to therapy was evaluated, 15 patients (75%) had stable disease (Figure 1). One patient progressed at the first restaging scan and subsequently came off trial treatment. Of the two patients who achieved partial response, one progressed 10 months and one died of a likely ventricular arrhythmia related to myocardial metastases 8 months after response.
Figure 1.
Waterfall plot depicting best percentage response of target lesions per RECIST 1.1.
As the study did not meet the interim analysis requirement for four objective responders in the first stage of enrollment, the study was closed to accrual after completion of stage 1 enrollment.
Progression-free and overall survival
All patients were assessable for survival analysis. At the time of data cut-off on 8 August 2023, 9 patients died and 11 patients remain alive and on follow-up. Median duration of follow-up is 19 months. Median PFS was 8 months (95% CI 5.8-10.2 months) (Figure 2), and median OS was not reached.
Figure 2.
Progression-free survival (n = 20).
Safety analysis
Overall, the safety profile of pembrolizumab and lenvatinib was similar to that reported in other cancers. The most commonly occurring drug-related AEs included hypertension, fatigue, abdominal pain, diarrhea, headache (often associated with hypertension), hypothyroidism, and adrenal insufficiency. Table 2 outlines all treatment-related toxicities.
Seventeen of 20 patients required modification of at least one drug dosage or schedule. Five patients required dose reduction of lenvatinib to 8 mg (lowest dose allowed on trial), three of whom still could not tolerate the dose reduction and needed to come off lenvatinib altogether; two of those patients continued on pembrolizumab monotherapy. Most common reasons for dose reduction included uncontrolled hypertension, significant abdominal pain, fatigue, or palmar-plantar erythrodysesthesia syndrome.
The chief toxicity attributed to lenvatinib was hypertension. Ten patients (50%) had grade 3 hypertension, often starting immediately after initiation of treatment. Six patients experienced hypothyroidism attributable to either pembrolizumab or lenvatinib and requiring administration of thyroid hormone. Other endocrine toxicities attributed to pembrolizumab included brittle insulin-dependent diabetes in one patient and adrenal insufficiency in one patient.
Of the three patients who died on study, one was a responder who likely developed ventricular arrhythmia related to myocardial metastases; her death was deemed unlikely related to study drug. The two other deaths were attributable to progressive disease.
Correlative studies
If available, archival tissue was sent to QualTek for central PD-L1 testing and evaluation of TILs. Thirteen patients had archival tissue available. Three of the 13 patients had PD-L1-positive staining [PD-L1 score of 3 and 2 (range 0-100)], none of whom responded to treatment. TILs were scored from 0 to 3, and nine patients had the presence of TILs on specimens. Five patients had a score of 1, one with a score of 2, and three with a score of 3.
Discussion
Our phase II trial of pembrolizumab plus lenvatinib for GI/thoracic NETs did not meet the interim radiographic response threshold required to proceed beyond stage 1 of the Simon two-stage design. Indeed, the observed response rate of 10% was mildly lower than that seen with lenvatinib monotherapy in a similar population of patients treated on the GETNE study (15%). No patient experienced a dramatic objective response of the sort that would indicate activation of T cells and immune cytotoxicity. Thus, we were unable to demonstrate that lenvatinib, when added to pembrolizumab, might reverse the immunosuppressive tumor microenvironment of well-differentiated NETs.
Toxicities were as expected for both pembrolizumab and lenvatinib, although we observed a higher rate of grade 3 hypertension than typically reported with lenvatinib alone or in combination with pembrolizumab. While pembrolizumab-associated AEs were rare, some were significant, including rare endocrinopathies such as brittle insulin-dependent diabetes and adrenal insufficiency. Our data add to evidence that CPI therapy should not be prescribed to unselected patients with well-differentiated NETs.
New strategies are needed to advance immunotherapy in well-differentiated NETs. Among these strategies are chimeric antigen receptor-T cells and bispecific T-cell engagers targeting the somatostatin receptor which is expressed by most well-differentiated NETs.26 Other approaches include identification of neoantigen-expressing tumors which may be selected for immune CPI therapy.
In conclusion, the combination of pembrolizumab and lenvatinib did not demonstrate activity in well-differentiated NETs beyond the expected response to lenvatinib. New treatment strategies are needed to activate antitumor immune response in this population.
Acknowledgments
Funding
Merck provided the funding to conduct this clinical trial, including both the pembrolizumab and the lenvatinib (no grant number).
Disclosure
The authors have declared no conflicts of interest.
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