Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies

Figures & data

Figure 1. The mechanisms of action of lenvatinib and its combination therapies^a: (A) lenvatinib and pembrolizumab; (B) lenvatinib, pembrolizumab, and chemotherapy; (C) lenvatinib and everolimus [21,23,25,30,31,35,36,38]. ^aFigure 1A reprinted from Oncology, Vol number 93, Kudo M, Immuno-Oncology in Hepatocellular Carcinoma: 2017 Update, pages 147–159, 2017, with permission from S. Karger AG, Basel. Figure 1B reprinted from Cell Press, Vol number 39, Chen DS and Mellman I, Oncology Meets Immunology: The Cancer-Immunity Cycle, pages 1–10, 2013, with permission from Elsevier. Figure 1C: Therapeutics & Clinical Risk Management 2017:13,799–806. Adapted and originally published by and used with permission from Dove Medical Press Ltd.

Table 1. Studies with lenvatinib dose escalations

Study (number of patients, tumor type)	Lenvatinib dosing and schedule	Dose; Dose-limiting toxicities (number of patients)	Lenvatinib maximum tolerated dose/recommended phase II dose	Efficacy outcomes(number of patients)	References
Study 101 (n = 82; solid tumors)	Daily, 28-day cycles 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.5, 16, 20, 25, 32 mg	6.4 mg daily: grade 3 febrile neutropenia (n = 1 of 21) 12.5 mg daily: grade 4 thrombocytopenia (n = 1 of 30) 16 mg daily: grade 3 hypertension and grade 3 fatigue (n = 1 of 30) 32 mg daily: grade 3 proteinuria (n = 2 of 7)	25 mg daily	SD^a: 46% (n = 38 of 82)	[40]
Study 102 (n = 77; solid tumors, lymphoma, and melanoma)	Schedule 1 (n = 18): twice daily, 7 days on/7 days off 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 mg Schedule 2 (n = 33): twice daily, continuous 3.2, 5.0, 8.0, 12.0 mg Melanoma cohort (n = 26): twice daily, continuous 10 mg	Schedule 1: none Schedule 2, 12 mg twice daily: grade 3 hypertension (n = 3 of 7); grade 3 fatigue (n = 1 of 7); grade 2 proteinuria (n = 1 of 7) Melanoma cohort: none (of 6)	10 mg twice daily	ORR^b: 11.7% (n = 9 of 77) SD^b: 51.9% (n = 40 of 77)	[42]
Study 103 (n = 27; solid tumors)	Twice daily, 2-week-on/ 1-week-off cycle 0.5, 1, 2, 4, 6, 9, 13, 16, 20 mg	16 mg twice daily: grade 3 AST/ALT increase (n = 1 of 3) 20 mg twice daily: grade 3 platelet count decrease (n = 2 of 2)	13 mg twice daily	ORR^a: 4% (n = 1 of 25) SD^a: 84% (n = 21 of 25)	[43]
Study 105 (n = 9; solid tumors)	Daily, continuous schedule 20 mg (n = 3) 24 mg (n = 6)	None	–	ORR^c: 11% (n = 1 of 11) SD^c: 45.5% (n = 5 of 11)	[41]
Study 202 phase I (n = 20; HCC)	CP A (n = 9): 12 mg daily, with escalation to 16 mg daily, then to 20 mg daily CP B (n = 11): lowest tolerable dose from CP A A lower dose level of 8 mg daily was planned for both CP A and CP B if 12 mg daily was not tolerable	12 mg daily (CP A): grade ≤2 fever/vomiting (n = 1 of 6) 16 mg daily (CP A): grade 3 proteinuria (n = 1 of 3); grade 3 hepatic encephalopathy (n = 1 of 3) 12 mg (CP B): grade 3 hepatic encephalopathy (n = 1 of 5); grade 3 increased AST, grade 3 hyperbilirubinemia, grade 2 increased creatinine (n = 1 of 5) 8 mg (CP B): none (of 6)	CP A: 12 mg dailyCP B: 8 mg daily	ORR^c (CP A): 22.2% (n = 2 of 9) SD^c (CP A): 44.4% (n = 4 of 9) ORR^c (CP B): 9.1% (n = 1 of 11) SD^c (CP B): 54.5% (n = 6 of 11)	[54]
Study 205 phase Ib (n = 20; RCC)	12 mg daily (n = 7), 18 mg daily (n = 11), 24 mg daily (n = 2), all + everolimus 5 mg daily	12 mg daily: grade 3 abdominal pain (n = 1 of 7)18 mg daily: failure to administer >75% of planned dose due to grade 3 elevated creatinine phosphokinase, grade 2 fatigue, and grade 1 reflux (n = 1 of 11) 24 mg daily: grade 3 nausea and vomiting (n = 1 of 2); failure to administer >75% of planned dose due to grade 2 mucosal inflammation (n = 1 of 2)	18 mg daily (with everolimus 5 mg daily)	ORR^c (12 mg daily): 28.6% (n = 2 of 7) SD^c (12 mg daily): 57.1% (n = 4 of 7) ORR^c (18 mg daily): 36.4% (n = 4 of 11) SD^c (18 mg daily): 45.5% (n = 5 of 11) ORR^c (24 mg daily): 0% (n = 0 of 2) SD^c (24 mg daily): 50.0% (n = 1 of 2)	[66]
Study 111/ KEYNOTE-146 phase Ib/phase II initial expansion (n = 137; solid tumors)	24 mg daily (n = 3), 20 mg daily (n = 134), both + pembrolizumab 200 mg every 3 weeks	24 mg daily: grade 3 arthralgia (n = 1 of 3) and grade 3 fatigue (n = 1 of 3) 20 mg daily: none (of 10)	20 mg daily (with pembrolizumab 200 mg every 3 weeks)	ORR at week 24^d RCC: 63% (n = 19 of 30) EC: 52% (n = 12 of 23) Melanoma: 48% (n = 10 of 21) SCCHN: 36% (n = 8 of 22) NSCLC: 33% (n = 7 of 21) UC: 25% (n = 5 of 20) SD (overall)^d RCC: 27% (n = 8 of 30) EC: 44% (n = 10 of 23) Melanoma: 33% (n = 7 of 21) SCCHN: 46% (n = 10 of 22) NSCLC: 48% (n = 10 of 21) UC: 45% (n = 9 of 20)	[61]
LEAP-006 safety run-in (n = 13; NSCLC)	8 mg daily (n = 13), + pembrolizumab 200 mg every 3 weeks + carboplatin or cisplatin and pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles) followed by lenvatinib 8 mg daily (with pembrolizumab 200 mg every 3 weeks [up to 35 cycles] + pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles)	With cisplatin: grade 3 hyponatremia (n = 2 of 6)	8 mg daily (with pembrolizumab 200 mg every 3 weeks + carboplatin or cisplatin and pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles) followed by lenvatinib 8 mg daily (with pembrolizumab 200 mg every 3 weeks [up to 35 cycles] + pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles)	ORR^c: 69.2% (n = 9 of 13) SD: 23.1% (n = 3 of 13)	[75]

^aper RECIST; ^bper RECIST (version 1.0); ^cper RECIST (version 1.1); ^dper immune-related RECIST.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CP = Child-Pugh; EC = endometrial carcinoma; HCC = hepatocellular carcinoma; NSCLC = non-small cell lung cancer; ORR = objective response rate; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria In Solid Tumors; SCCHN = squamous cell carcinoma of head and neck; SD = stable disease; UC, urothelial cancer.

Table 2. Studies with phase II evaluations of lenvatinib

Study (number of patients, tumor type)	Lenvatinib dosing and schedule	Primary efficacy outcomes	Other outcomes	References
Study 202 (n = 46; HCC)	CP A: 12 mg daily	TTP (median [95% CI]) 7.4 months (5.5–9.4)	ORR (n of n) per mRECIST 37% (17 of 46) OS (median [95% CI]) 18.7 months (12.7–25.1)	[55]
Study 205 (n = 153; RCC)	18 mg daily (n = 51) + everolimus 5 mg daily, 24 mg daily (n = 52) (monotherapy),(everolimus 10 mg daily [n = 50] [monotherapy])	PFS (median [95% CI]) per RECIST version 1.1 Lenvatinib + everolimus: 14.6 months (5.9–20.1)Lenvatinib monotherapy: 7.4 months (5.6–10.2)Everolimus monotherapy: 5.5 months (3.5–7.1) HR 0.40; 95% CI 0.24–0.68; P = 0.0005 (lenvatinib + everolimus vs everolimus monotherapy) HR 0.66; 95% CI 0.39–1.10; P = 0.12 (lenvatinib + everolimus vs lenvatinib monotherapy)	ORR (n of n) per RECIST version 1.1 Lenvatinib + everolimus: 43% (22 of 51)Lenvatinib monotherapy: 27% (14 of 52) Everolimus monotherapy: 6% (3 of 50) OS (median [95% CI]) Lenvatinib + everolimus: 25.5 (16.4–NE)Lenvatinib monotherapy: 19.1 (13.6–26.2) Everolimus monotherapy: 15.4 (11.8–19.6)	[9]
Study 111/KEYNOTE-146 (phase II expansion) (n = 108; previously treated EC)	20 mg daily + pembrolizumab 200 mg every 3 weeks	ORR at week 24 (n of n; 95% CI) per irRECISTMSS/pMMR: 36.2% (34 of 94; 26.5–46.7) MSI-H/dMMR: 63.6% (7 of 11; 30.8–89.1) Overall: 38.0% (41 of 108; 28.8–47.8)	Overall PFS (median [95% CI]) per irRECIST 7.4 months (5.3–8.7) Overall OS (median [95% CI]) 16.7 months (15.0–NE)	[63]
Study 111/KEYNOTE-146 (phase II expansion) (n = 143; RCC)	20 mg daily + pembrolizumab 200 mg every 3 weeks	ORR at week 24 (n of n; 95% CI) per irRECISTTreatment naïve: 72.7% (16 of 22; 49.8–89.3) Previously treated, ICI-naïve: 41.2% (7 of 17; 18.4–67.1) ICI pretreated: 55.8% (58 of 104; 45.7–65.5)	PFS (median [95% CI]) per irRECIST ICI pretreated: 12.2 months (9.5–17.7) OS (median [95% CI]) ICI pretreated: NR (NR–NR)	[65]
REMORA (Japan)(n = 42; unresectable thymic carcinoma)	24 mg daily in 4-week cycles	ORR (n of n; 90% CI) per RECIST version 1.1 38% (16 of 42; 25.6–52.0)	Overall PFS (median [95% CI]) per RECIST version 1.1 9.3 months (7.7–13.9) Overall OS (median [95% CI]) NR (16.1–NR)	[60]
Dose-comparison studies
Study 211 (n = 152; RR-DTC)(Data on file, Eisai Inc.)	24 mg daily (n = 75), 18 mg daily (n = 77)	ORR at week 24 (n of n; 95% CI) per RECIST version1.1^a 18 mg: 40.3% (31 of 77; 29.3–51.2) 24 mg: 57.3% (43 of 75; 46.1–68.5) Odds ratio 0.50 (95% CI 0.26–0.96)	Overall ORR (n of n) per RECIST version 1.1 18 mg: 46.8% (36 of 77) 24 mg: 64% (48 of 75) PFS^b (median [95% CI]) per RECIST version 1.1 18 mg: 24.4 months (14.7–NE) 24 mg: NR (22.1–NE) HR (18 mg vs 24 mg) 1.44 (95% CI 0.76–2.74) Stratified^c log-rank P = 0.2648 OS (median [95% CI]) NR (NE) for both arms HR (18 mg vs 24 mg) 1.26 (95% CI 0.55–2.89) Stratified^c log-rank P = 0.5867	[59]
Study 218 (n = 311; RCC)(Data on file, Eisai Inc.)	14 mg (n = 156), 18 mg (n = 155), Both + everolimus 5 mg daily	ORR at week 24 (n of n; 95% CI) per RECIST version 1.1^d 14 mg: 32.1% (50 of 156; 24.7–39.4)18 mg: 34.8% (54 of 155; 27.3–42.3)Odds ratio 0.88 (95% CI 0.59–1.32); P (1-sided) = 0.2676	Overall ORR (n of n) per RECIST version 1.1 14 mg: 34.6% (54 of 156)18 mg: 40.6% (63 of 155) PFS^e (median, 95% CI) per RECIST version 1.1 14 mg: 11.1 months (9.0–12.9) 18 mg: 14.7 months (11.1–20.3) HR^f (14 mg vs 18 mg) 1.42 (95% CI 1.08–1.86) OS (median [95% CI]) 14 mg: 27.0 months (18.3–NE) 18 mg: NE (23.8–NE) HR^f (14 mg vs 18 mg) 1.20 (95% CI 0.87–1.65)	[67]

^aNoninferiority margin is 0.4 based on odds ratio. Noninferiority could be claimed if the lower bound of the 95% CI of odds ratio for ORR at week 24 of treatment (18 mg/24 mg daily doses) > 0.4. ^bThe primary safety endpoint was TEAEs of grade ≥3 in the first 24 weeks after randomization (24 mg arm: 61.3%; 18 mg arm: 57.1%). Most common TEAEs: 24 mg arm: hypertension (57.3%), diarrhea (56.0%), weight decreased (36.0%); 18 mg arm: hypertension (51.9%), diarrhea (51.9%), weight decreased (42.9%). Discontinuation of lenvatinib due to TEAEs: 24 mg dose: 14.7%; 18 mg dose: 16.9%. Reduction of lenvatinib due to TEAEs: 24 mg dose: 69.3%; 18 mg dose: 59.7%.

^cStratified by the randomization stratification factors (ECOG PS: 0 vs 1 or 2; age group: ≤65 vs >65 years).

^dNoninferiority margin is 0.76 based on odds ratio of objective response rate at week 24. Noninferiority could be claimed if the P (1-sided) < 0.045 for noninferiority testing of odds ratio for ORR at week 24 (14 mg/18 mg daily doses) after adjusting for 2 interim analyses. Analysis included patients in the per-protocol analysis set 1.

^eThe primary safety endpoint was intolerable grade 2 or any grade ≥3 TEAEs within 24 weeks of randomization (18 mg arm: 79.6%; 14 mg arm: 82.8%). Most common TEAEs: 18 mg arm: diarrhea (72.0%), hypertension (35.7%), proteinuria (35.7%); 14 mg arm: diarrhea (68.2%), decreased appetite (35.3%), stomatitis (34.1%).

^fStratified by MSKCC prognostic group and prior PD-1/PD-L1 treatment from IxRS data. For MSKCC prognostic group from IxRS, the poor risk group is pooled with the intermediate risk group in the model. Hazard ratio of lenvatinib 14 mg over lenvatinib 18 mg was based on a Cox Proportional Hazard Model including treatment group as a factor, Efron method is used for ties.

CI = confidence interval; CP = Child-Pugh; dMMR = mismatch repair-deficient; EC = endometrial carcinoma; ECOG PS = Eastern Cooperative Oncology Group performance status; HCC = hepatocellular carcinoma; HR = hazard ratio; ICI = immune checkpoint inhibitor; irRECIST = immune-related RECIST; IV = intravenously; IxRS = Interactive Voice/Web Response System; mRECIST = modified RECIST; MSI-H = high levels of microsatellite instability; MSKCC = Memorial Sloan Kettering Cancer Center; MSS = microsatellite stable; MTD = maximum tolerated dose; NE = not estimable; NR = not reached; ORR = objective response rate; OS = overall survival; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PFS = progression-free survival; pMMR = mismatch repair-proficient; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria In Solid Tumors; RR-DTC = radioiodine-refractory differentiated thyroid carcinoma; TEAE = treatment-emergent adverse event; TTP = time to progression.

Table 3. Most common adverse events and dose modifications of lenvatinib in selected studies

Study	Tumor type and population	Lenvatinib dosing and schedule	Most common TEAEs or TRAEs	Lenvatinib discontinuations due to TEAEs/TRAEs (%)	Lenvatinib dose reductions/interruptions (%)	Median time to dose reductions	References
Study 111/KEYNOTE-146	RCC (n = 30); EC (n = 23); SCCHN (n = 22); Melanoma (n = 21); NSCLC (n = 21); UC (n = 20)	24 mg daily (n = 3)20 mg daily (n = 134) In combination with pembrolizumab 200 mg every 3 weeks	TRAEs Fatigue (58%)Diarrhea (52%) Hypertension (47%)	13% (due to TRAEs)	85% (reduction or interruption due to TRAEs)	~2 months	[61,63,65]
	EC expansion (n = 108)	20 mg daily In combination with pembrolizumab 200 mg every 3 weeks	TRAEs Hypertension (61.1%)Diarrhea (52.8%) Fatigue (51.9%)	–	–	–
	RCC expansion (n = 145)	20 mg daily In combination with pembrolizumab 200 mg every 3 weeks	TRAEs Fatigue (58.6%)Diarrhea (55.2%) Hypertension (40.0%)	13% (due to TRAEs)	65.0% (reduction due to TRAEs)	2.2 months (interquartile range 1.4–5.2)
Study 205	RCC (n = 51, lenvatinib + everolimus; n = 52, lenvatinib monotherapy)	18 mg daily In combination with everolimus 5 mg daily	TEAEs Diarrhea (84.3%) Decreased appetite (51.0%) Fatigue/asthenia (58.8%)	24% (due to TEAEs)	71% (reduction)	First reduction within the first 3 cycles: 49%	[9]
		24 mg daily (monotherapy)	TEAEs Diarrhea (71.2%)Nausea (61.5%)Decreased appetite (57.7%)	25% (due to TEAEs)	62% (reduction)	First reduction within the first 3 cycles: 38%
Study 303	RR-DTC (n = 261)	24 mg daily	TRAEs Hypertension (67.8%) Diarrhea (59.4%) Fatigue/asthenia (59.0%)	14.2% (due to TEAEs)	67.8% (reduction) 82.4% (interruption)	3.0 months (95% CI 2.7–3.7)	[3]
Study 304	uHCC (n = 476)	12 mg daily (patients ≥ 60 kg) 8 mg daily (patients < 60 kg)	TEAEs Hypertension (42%) Diarrhea (39%) Decreased appetite (34%)	9% (due to TRAEs)	37% (reduction due to TRAEs) 40% (interruption due to TRAEs)	–	[4]
Study 309/KEYNOTE-775	EC (n = 406, lenvatinib + pembrolizumab population only)	20 mg daily In combination with pembrolizumab 200 mg IV every 3 weeks	TEAEs Hypertension (64.0%) Hypothyroidism (57.4%) Diarrhea (54.2%)	30.8% (due to TEAEs)	66.5% (reduction due to TEAEs) 58.6% (interruption due to TEAEs)	1.9 months (range 0.1–22.8)	[8]
Study 307/KEYNOTE-581	RCC (n = 352, lenvatinib + pembrolizumab population only)	20 mg daily In combination with pembrolizumab 200 mg IV every 3 weeks	TEAEs Diarrhea (61.4%) Hypertension (55.4%) Hypothyroidism (47.2%)	25.6% (due to TEAEs)	68.8% (reduction due to TEAEs)	–	[6]

AE = adverse event; CI = confidence interval; EC = endometrial carcinoma; IV = intravenously; NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma; RR-DTC = radioiodine-refractory differentiated thyroid carcinoma; SCCHN = squamous cell carcinoma of the head and neck; TEAE = treatment-emergent adverse event; TRAE = treatment-related adverse event; UC = urothelial cancer; uHCC = unresectable hepatocellular carcinoma.

Table 4. Phase III trials of lenvatinib as monotherapy or combination therapy

Study (N)	Tumor type	Regimens	Progression-free survival Median, months (95% CI)	Overall survival Median, months (95% CI)	Objective response rate % (n of n)	References
SELECT (Study 303, N = 392)	RR-DTC	Lenvatinib 24 mg daily or placebo	Lenvatinib^a: 18.3 (15.1–NE) Placebo^a: 3.6 (2.2–3.7) HR (lenvatinib vs placebo) 0.21 (99% CI 0.14–0.31); P < 0.001	Lenvatinib: NR Placebo: NR HR (lenvatinib vs placebo) 0.73 (95% CI 0.50–1.07); P = 0.10^b	Lenvatinib^a: 64.8% (169 of 261) Placebo^a: 1.5% (2 of 131) Odds ratio (lenvatinib vs placebo) 28.87 (95% CI 12.46–66.86); P < 0.001	[3]
REFLECT (Study 304, N = 954)	uHCC	Lenvatinib 12 mg daily (≥ 60 kg) 8 mg daily (< 60 kg) or sorafenib 400 mg twice daily	Lenvatinib^c: 7.4 (6.9–8.8) Sorafenib^c: 3.7 (3.6–4.6) HR (lenvatinib vs sorafenib) 0.66 (95% CI 0.57–0.77); Log-rank P < 0.0001	Lenvatinib: 13.6 (12.1–14.9) Sorafenib: 12.3 (10.4–13.9) HR (lenvatinib vs sorafenib) 0.92 (95% CI 0.79–1.06)	Lenvatinib^c: 24.1% (115 of 478) Sorafenib^c: 9.2% (44 of 476) Odds ratio (lenvatinib vs sorafenib) 3.13 (95% CI 2.15–4.56); P < 0.0001	[4]
CLEAR (Study 307/ KEYNOTE-581,N = 1069)	aRCC	Lenvatinib 20 mg daily + pembrolizumab 200 mg every 3 weeks or Lenvatinib 18 mg daily + everolimus 5 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off)	Lenvatinib + pembrolizumab^a: 23.9 (20.8–27.7) Lenvatinib + everolimus^a: 14.7 (11.1–16.7) Sunitinib^a: 9.2 (6.0–11.0) HR (lenvatinib + pembrolizumab vs sunitinib): 0.39 (95% CI 0.32–0.49); P < 0.001	Lenvatinib + pembrolizumab: NR (33.6–NE) Lenvatinib + everolimus: NR (NE–NE) Sunitinib: NR (NE–NE) HR (lenvatinib + pembrolizumab vs sunitinib): 0.66 (95% CI 0.49–0.88); P = 0.005	Lenvatinib + pembrolizumab^a: 71.0% Lenvatinib + everolimus^a: 53.5% Sunitinib: 36.1% Relative risk (lenvatinib + pembrolizumab vs sunitinib): 1.97 (95% CI 1.69–2.29)	[6]
Study 309/ KEYNOTE-775 (N = 827)	aEC	Lenvatinib 20 mg daily + pembrolizumab 200 mg every 3 weeks or chemotherapy (doxorubicin 60 mg/m^2 every 3 weeks or paclitaxel 80 mg/m^2 every week (3 weeks on/1 week off)	All patients (irrespective of MMR status) Lenvatinib + pembrolizumab^a: 7.2 (5.7–7.6) Chemotherapy^a: 3.8 (3.6–4.2) HR (lenvatinib + pembrolizumab vs chemotherapy) 0.56 (95% CI 0.47–0.66); P < 0.001 pMMR group Lenvatinib + pembrolizumab^a: 6.6 (5.6–7.4) Chemotherapy^a: 3.8 (3.6–5.0) HR (lenvatinib + pembrolizumab vs chemotherapy) 0.60 (95% CI 0.50–0.72); P < 0.001	All patients (irrespective of MMR status) Lenvatinib + pembrolizumab: 18.3 (15.2–20.5) Chemotherapy: 11.4 (10.5–12.9) HR (lenvatinib + pembrolizumab vs chemotherapy) 0.62 (95% CI 0.51–0.75); P < 0.001 pMMR group Lenvatinib + pembrolizumab: 17.4 (14.2–19.9) Chemotherapy: 12.0 (10.8–13.3) HR (lenvatinib + pembrolizumab vs chemotherapy) 0.68 (95% CI 0.56–0.84); P < 0.001	All patients (irrespective of MMR status) Lenvatinib + pembrolizumab^a: 31.9% Chemotherapy^a: 14.7% pMMR group Lenvatinib + pembrolizumab^a: 30.3% Chemotherapy^a: 15.1%	[8]
LEAP-006 (N = 13)^d	NSCLC	Lenvatinib 8 mg daily or matching placebo, all + pembrolizumab 200 mg every 3 weeks + carboplatin or cisplatin and pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles followed by lenvatinib 8 mg daily + pembrolizumab 200 mg every 3 weeks (up to 35 cycles) + pemetrexed 500 mg/m^2 every 3 weeks x 4 cycles	Not available	Not available	Not available	[75]

^aPer RECIST version 1.1. ^bWhen a potential crossover bias was considered, the median OS was not reached for both arms and adjusted HR was 0.62 (95% CI 0.40–1.00); P = 0.05. ^cinvestigator review per mRECIST. ^dEnrollment is ongoing for Part 2. Data from the safety run-in (Part 1) is included in Table 1.

aEC = advanced endometrial carcinoma; aRCC = advanced renal cell carcinoma; CI = confidence interval; HR = hazard ratio; MMR = mismatch repair; mRECIST; modified RECIST; NE = not estimable; NR = not reached; NSCLC = non-small cell lung cancer; pMMR = mismatch repair-proficient; RECIST = Response Evaluation Criteria In Solid Tumors; RR-DTC = radioiodine-refractory differentiated thyroid carcinoma; SD = standard deviation; uHCC = unresectable hepatocellular carcinoma.

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