Combination Therapy Demonstrates Promising Antitumor Activity

A PAIR OF TRIALS evaluating multikinase inhibition with lenvatinib (Lenvima; Eisai) plus pembrolizumab (Keytruda; Merck) have found promising antitumor activity.¹

The 2 trials, KEYNOTE-524 (NCT02980731) and KEYNOTE-146 (NCT02980731), examined patients with unresectable hepatocellular carcinoma (uHCC) with no prior systemic therapy and patients with metastatic clear cell renal cell carcinoma (mccRCC), who progressed following immune checkpoint inhibitor (ICI) therapy, respectively.¹ These study results were announced by Eisai and Merck during the 2020 American Society of Clinical Oncology Virtual Scientific Program, May 29-31, in a poster and oral abstract session, respectively.

Lenvatinib is an orally available multiple receptor tyrosine kinase inhibitor developed by Eisai. Pembrolizumab is an anti—PD-1 therapy from Merck.¹

KEYNOTE-524 examined multikinase inhibition with lenvatinib plus PD-1 inhibition with pembrolizumab and found a high objective response rate (46% by modified RECIST [mRECIST] and 36% by RECIST v1.1) and disease control rate (88% by both mRECIST and RECIST v1.1). There were no new or unexpected toxicities with this combination therapy.²

In KEYNOTE-146, researchers found consistent overall response rate (ORR) (55%) per immune-related RECIST (irRECIST) and median progression-free survival (PFS) (11.7 months) per irRECIST in patients with mccRCC who had experienced disease progression following prior PD-1/ PD-L1 ICI therapy, and who had used lenvatinib plus pembrolizumab. ORR and median PFS were consistent between irRECIST and RECIST v1.1, and across treatment subgroups.³

According to Merck representatives, the tumor response rates demonstrated with the lenvatinib/ pembrolizumab therapy in the 2 studies underscore the potential of this combination regimen in certain types of HCC and RCC.¹

“As data from our combination trials continue to read out, our enthusiasm for and belief in the potential of Lenvima plus Keytruda are strengthened by the growing body of evidence observed in multiple advanced cancers,” Takashi Owa, PhD, chief medicine creation officer and chief discovery officer for Eisai’s Oncology Business Group, said in a news release.¹

KEYNOTE-524 Trial^1,2

KEYNOTE-524 is a phase 1b, open-label, single-arm trial evaluating the lenvatinib plus pembrolizumab combination in 100 patients with uHCC with no prior systemic therapy. Patients were treated with lenvatinib 8 or 12 mg (based on baseline body weight) orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks.

The primary end points are ORR and duration of response (DOR) by modified mRECIST and RECIST v1.1 per independent imaging review (IIR). Secondary end points include PFS, time to progression, and overall survival (OS). At data cutoff (October 31, 2019) and a median duration of follow-up of 10.6 months (95% CI, 9.2-11.5), 37 patients were still on study treatment (lenvatinib plus pembrolizumab: n = 34; lenvatinib only: n = 3), and median duration of treatment exposure to the lenvatinib plus pembrolizumab combination was 7.9 months (range, 0.2-31.1).

The final analysis of the study’s primary end points showed that the lenvatinib plus pembrolizumab combination demonstrated an ORR of 36% (n = 36; 95% CI, 26.6-46.2), with a complete response rate of 1% (n = 1), a partial response rate of 35% (n = 35), and a median DOR of 12.6 months (95% CI, 6.9-not estimable [NE]), using RECIST v1.1 criteria per IIR.

As assessed using mRECIST criteria per IIR, the lenvatinib plus pembrolizumab combination demonstrated an ORR of 46% (n = 46; 95% CI, 36.0%-56.3%), with a complete response rate of 11% (n = 11), a partial response rate of 35% (n = 35), and a median DOR of 8.6 months (95% CI, 6.9-NE).

In this study, treatment-related adverse events (trAEs) led to discontinuation of lenvatinib and pembrolizumab in 6% of patients, of lenvatinib in 14% of patients, and of pembrolizumab in 10% of patients. Grade ≥3 trAEs occurred in 67% of patients (grade 3: 63%; grade 4: 1%; grade 5: 3%).

There was a single grade-4 trAE (leukopenia/neutropenia) and 3 treatment-related deaths (acute respiratory failure/acute respiratory distress syndrome, intestinal perforation, and abnormal hepatic function; n = 1 for each). The most common trAEs of any grade (≥20%) were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar-plantar erythrodysesthesia syndrome (23%), decreased weight (22%), dysphonia (21%), increased aspartate aminotransferase (20%) and proteinuria (20%).

KEYNOTE-146 Trial^1,3

KEYNOTE-146 is a phase 1b/2, open-label, single-arm trial evaluating the lenvatinib plus pembrolizumab combination in patients with selected solid tumors. Results from the RCC cohort of the phase 2 part of the study are based on 104 patients with mccRCC with disease progression following PD-1/PD-L1 ICI therapy using RECIST v1.1 criteria.

Patients were treated with lenvatinib 20 mg orally once daily in combination with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or disease progression. The primary end point is ORR at week 24 by irRECIST per investigator review. The key secondary end points include ORR, PFS, OS, safety, and tolerability for a maximum of 35 cycles/treatments, or approximately 2 years.

At data cutoff, April 9, 2020, results from the phase 2 part of the study showed that the combination therapy demonstrated an ORR at week 24 of 51% (95% CI, 41%-61%) by irRECIST per investigator review. As assessed by irRECIST per investigator review, ORR was 55% (95% CI, 45%-65%), with a partial response rate of 55%, stable disease rate of 36%, and progressive disease rate of 5% (5% were not evaluable). Median DOR was 12 months (95% CI, 9-18). Median PFS was 11.7 months (95% CI, 9.4-17.7), and the 12-month PFS rate was 45% (95% CI, 32%-57%). Median OS was not reached (95% CI, 16.7-NR), and the 12-month OS rate was 77% (95% CI, 67%-85%).

As assessed by RECIST v1.1 per investigator review, ORR was 52% (95% CI, 42%-62%), with a partial response rate of 52%, stable disease rate of 38%, and progressive disease rate of 6% (5% were NE). Median DOR was 12 months (95% CI, 9-18). Median PFS was 11.3 months (95% CI, 7.6-17.7), and the 12-month PFS rate was 44% (95% CI, 31%-55%).

In this study, trAEs led to discontinuation of lenvatinib and pembrolizumab in 15% of patients, discontinuation of lenvatinib in 12% of patients, and discontinuation of pembrolizumab in 12% of patients (2% due to proteinuria). Grade 4 trAEs included increased lipase, diverticulitis, large intestine perforation, and myocardial infarction, and grade 5 trAEs included upper gastrointestinal hemorrhage and sudden death.

In both studies, the most common trAEs of any grade (≥20%) were fatigue, diarrhea, proteinuria, dysphonia, hypertension, decreased appetite, palmar-plantar erythrodysesthesia syndrome, and hypothyroidism.1-3 Additionally, decreased weight and increased aspartate aminotransferase were common trAEs found in KEYNOTE-524.1,2 Other common trAEs found in KEYNOTE-146 were nausea, stomatitis, arthralgia, and headache.^1,3

According to the investigators, ongoing phase 3 trials are continuing to explore the use of lenvatinib plus pembrolizumab as a cancer therapy.2,3 The combination is being evaluated as a first-line option for patients with uHCC in the LEAP-002 study (NCT03713593)2 and as a first-line treatment for advanced RCC in the NCT02811861 trial.³

REFERENCES

• Results from Lenvima (lenvatinib) plus Keytruda (pembrolizumab) trials in unresectable hepatocellular carcinoma and advanced renal cell carcinoma to be presented at 2020 ASCO Annual Meeting. News release. Eisai; May 29, 2020. Accessed June 12, 2020. https://www.eisai.com/news/2020/news202023.html
• Zhu A, Finn RS, Ikeda M, et al. A phase 1b study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma (uHCC). Poster presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program, May 29-31, 2020.
• Lee C-H, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). Oral abstract presented at: American Society of Clinical Oncology 80th Virtual Scientific Program, May 29-31, 2020. https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.5008