FDA Issues Complete Response Letter for Pembrolizumab/Lenvatinib in First-Line HCC

The FDA has issued a complete response letter to Merck and Eisai stating that it will not approve the applications that are seeking the accelerated approval of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC).¹

The applications had been based on findings from the phase 1b KEYNOTE-524/Study 116 trial, which had demonstrated that the combination resulted in clinically meaningful efficacy in the single-arm setting. However, ahead of the Prescription Drug User Fee Act (PDUFA) action dates for the applications, another combination therapy, atezolizumab (Tecentriq) plus bevacizumab (Avastin) received regulatory approval based on data that demonstrated overall survival benefit.

The FDA noted in the response letter that in light of these developments, the applications submitted for the pembrolizumab/lenvatinib combination do not provide evidence to indicate that this combination offers a meaningful advantage over other options available for patients with unresectable or metastatic HCC who have not received previous systemic treatment for advanced disease.

In July 2019, the FDA had granted a breakthrough therapy designation to the combination based on earlier data from KEYNOTE-524/Study 116. Interim data indicated that the combination induced an investigator-assessed overall response rate (ORR) of 36.7% via modified RECIST criteria in patients with unresectable disease.²

Updated data presented during the 2020 ASCO Virtual Scientific Program demonstrated a high ORR of 46% (95% CI, 36.0-56.3) via modified RECIST criteria per independent imaging review (IIR) and 36% (95% CI, 26.6-46.2) via RECIST version 1.1 per IIR.³ The median duration of response (DOR) via both of these criteria was 8.6 months (95% CI, 6.9–not evaluable [NE]) and 12.6 months (95% CI, 6.9-NE), respectively, and the median time to response was 1.9 months (95% CI, 1.2-5.5) versus 2.8 months (95% CI, 1.2-7.7), respectively. Furthermore, the disease control rate with the combination via both of these criteria was 88% (95% CI, 80.0%-93.6%, for both).

In the multicenter, open-label, single-arm trial, investigators examined the safety and effectiveness of the combination of pembrolizumab and lenvatinib in patients with unresectable disease. The PD-1 inhibitor was given intravenously at 200 mg every 3 weeks and lenvatinib was given at a daily dose of 12 mg for patients who weighed ≥60 kg, and 8 mg/day for those weighing <60 kg.

To be eligible for enrollment, patients must have had Barcelona Clinic Liver Cancer (BCLC) stage B disease that was ineligible for transarterial chemoembolization or C, Child-Pugh class A disease, and an ECOG performance status of either 0 or 1. The primary end points of the trial are tolerability and safety and key secondary end points include OS, ORR, progression-free survival (PFS) and time to progression (TTP) per modified RECIST criteria. Moreover, tumors were assessed for complete response (CR) or partial response (PR) ≥4 weeks after initial response.

In the first portion of the study, investigators evaluated dose-limiting toxicities (DLTs) during the first treatment cycle in patients for whom no other appropriate therapeutic options were available. After tolerability was confirmed, additional patients who had not received prior systemic therapy for unresectable disease were enrolled in the expansion phase of the trial. In the expansion phase, investigators are examining ORR and DOR, as measured by modified RECIST and RECIST 1.1 criteria based on IIR.

Notably, no DLTs had been reported in part 1 of the trial (n = 6). Thus, 24 patients with no prior systemic treatment were then enrolled into the expansion phase of the trial.

At the time of data cutoff, which was October 31, 2019, 37% (n = 37) were still receiving study treatment with both drugs. The median duration of exposure to the combination was 7.9 months (range, 0.2-31.1).

With regard to safety, the most common adverse effects (AEs) of any grade that were reported with the combination included hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), Palmar-plantar erythrodysesthesia syndrome (23%), weight decrease (22%), dysphonia (21%), increased aspartate aminotransferase (20%), and proteinuria (20%).

Grade ≥3 treatment-related AEs (TRAEs) were reported in 67 patients (grade 3, 3%; grade 4, 1%; and grade 5, 3%). The 3 grade 5 TRAEs included acute respiratory failure/acute respiratory distress syndrome (n = 1), abnormal hepatic function (n = 1), and intestinal perforation (n = 1); all are well described as potential toxicities for these drug classes. One grade 4 TRAE of leukopenia/neutropenia was reported.

TRAEs resulted in discontinuation of lenvatinib in 14% (n = 14) of patients, of pembrolizumab in 10% (n = 10) of patients, and of the combination in 6% (n = 6) of patients.

Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies announced that they will be working with the FDA to take the appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and clinical benefit with the pembrolizumab/lenvatinib combination.

To this end, the phase 3 LEAP-002 trial, which is examining the combination as a frontline treatment for patients with advanced HCC, is currently underway and has fully enrolled.

Notably, the complete response letter does not impact the current approved indications for the combination. In September 2019, the combination garnered an accelerated approval from the FDA for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are ineligible for curative surgery or radiation.

References

1. Merck and Eisai receive complete response letter for Keytruda (pembrolizumab) and Lenvima (lenvatinib) combination as first-line treatment for unresectable hepatocellular carcinoma. News release. Merck. July 8, 2020. Accessed July 8, 2020. bwnews.pr/2ZUmtDw.
2. Merck and Eisai receive third Breakthrough therapy designation from FDA for Keytruda (pembrolizumab) plus Lenvima (lenvatinib) combination treatment. News release. Merck. July 23, 2019. Accessed July 8, 2020. bit.ly/2Gq3nwi.
3. Zhu AX, Finn RS, Ikeda M, et al. A phase 1b study of lenvatinib and pembrolizumab in patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(suppl 15):4519. doi: 10.1200/JCO.2020.38.15_suppl.4519