Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

Multitargeted VEGFR tyrosine kinase inhibitors

17 evidence topics · 19 sources

ASCO guideline: multitargeted TKI when a clinical trial is not available

“For patients with ACC who are candidates for initiation systemic therapy, a multitargeted tyrosine kinase inhibitor (TKI), such as lenvatinib or sorafenib, may be offered if a clinical trial is not available.” (opens the source at this quote in a new tab)

ESMO-EURACAN guideline: angiogenesis inhibitors

“When starting systemic treatment, consider angiogenesis inhibitors [III, C] or platinum-based ChT (i.e. CAP or doxorubicin–cisplatin) [III, B].” (opens the source at this quote in a new tab)
“Antiangiogenic agents (sorafenib, lenvatinib and axitinib) have been investigated in recent years, but response rates did not exceed 15%” (opens the source at this quote in a new tab)
“In this context, axitinib was the first agent to demonstrate a significant PFS prolongation compared with placebo in a phase II randomised trial (hazard ratio 0.25, 95% CI 0.14-0.48),” (opens the source at this quote in a new tab)

NCCN Guidelines: lenvatinib and axitinib plus avelumab as category 2B options

“Based on these results and lack of other evidence-based options for recurrent or metastatic adenoid cystic carcinoma, lenvatinib is a category 2B option.” (opens the source at this quote in a new tab)

“These results led to the inclusion of axitinib plus avelumab in the National Comprehensive Cancer Network (NCCN) guidelines as a category 2B recommendation for recurrent/metastatic ACC” (opens the source at this quote in a new tab)

“VEGFR-targeting tyrosine kinase inhibitors, such as lenvatinib and axitinib, have shown encouraging disease control rates and are now considered standard options.” (opens the source at this quote in a new tab)

Lenvatinib: phase II trial in progressive R/M ACC

“Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response.” (opens the source at this quote in a new tab)
“Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed.” (opens the source at this quote in a new tab)

“Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported.” (opens the source at this quote in a new tab)
“The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively.” (opens the source at this quote in a new tab)

“Fifty-one patients were included across 17 Italian sites. Forty-six patients (90%) were evaluated for response: the ORR was 21.7%, with 10 patients achieving a partial response; 24 patients had a stable disease resulting in a disease control rate of 73.9%.” (opens the source at this quote in a new tab)

Axitinib: single-arm phase II trial and randomized phase II trial versus observation

“Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses.” (opens the source at this quote in a new tab)
“The median progression-free survival (PFS) was 5.7 months (range 0.92–21.8 months).” (opens the source at this quote in a new tab)

“Sixty patients were allocated to the axitinib or observation group, with response evaluation conducted in 54 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.0% with axitinib and 23.0% with observation. Median PFS was longer in the axitinib arm (10.8 months vs. 2.8 months, P < 0.001). The ORR of axitinib was 0.0%, but the disease control rate was 100.0% with axitinib and 51.9% with observation. Median OS was not reached with axitinib, but was 27.2 months with observation (P = 0.226).” (opens the source at this quote in a new tab)

Axitinib plus avelumab: phase II trial

“Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR).” (opens the source at this quote in a new tab)
“The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months).” (opens the source at this quote in a new tab)
“The potential added benefit of avelumab to axitinib in ACC requires further investigation.” (opens the source at this quote in a new tab)

Rivoceranib (apatinib): RM-202 phase II trial

“Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9–25.7] and 9.7% (95% CI, 4.0–19.0); median duration of response was 14.9 months (95% CI, 4.9–17.3) and 7.2 months (95% CI, 3.5–8.4); and median progression-free survival was 9.0 months (95% CI, 7.3–11.5) and 9.0 months (95% CI, 7.7–11.5).” (opens the source at this quote in a new tab)

Apatinib: single-arm phase II trial in China

“Among 68 patients treated with apatinib, 65 were evaluable for efficacy analysis, with a median follow-up time of 25.8 months. The 6-month, 12-month, and 24-month PFS rates were 92.3% [95% confidence interval (CI): 83–97.5%], 75.2% (95% CI: 61.5–84.0%) and 44.7% (95% CI: 32.3–57.5%), respectively. The objective response rate (ORR) and disease control rate (DCR), as assessed by investigators, were 46.2% (95% CI: 33.7–59.0%) and 98.5% (95% CI: 91.7–100.0%), respectively.” (opens the source at this quote in a new tab)

Sorafenib and dovitinib: phase II trials

“Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC).” (opens the source at this quote in a new tab)

“The 4-month PFS probability was 80.4%, and the median PFS was 6.0 months (95% confidence interval, 4.4-7.6 months). Tumor shrinkage was observed in 22 patients (68.8%), and 1 patient had a confirmed partial response. The disease control rate was 96.9%.” (opens the source at this quote in a new tab)

Meta-analysis of VEGFR inhibitors in R/M ACC: 17 studies, 560 participants

“A total of 17 studies comprising 560 patients with recurrent or metastatic ACC treated with 10 VEGFR inhibitors were included. The objective response rate was 6% (95% CI, 3%-12%; I2 = 71%) and stable disease was the most frequent best overall response (82%; 95% CI, 74%-87%; I2 = 67%). The 6-month disease control (defined as objective response and stable disease) rate was 54% (95% CI, 45%-62%; I2 = 52%).” (opens the source at this quote in a new tab)
“Rivoceranib had the highest objective response rate (24%; 95% CI, 7%-57%) but high heterogeneity among studies (I2 = 95%) and the lowest rate of patients who continued therapy until PD (35%; 95% CI, 20%-55%; I2 = 90%).” (opens the source at this quote in a new tab)

Axitinib versus observation: randomized phase II efficacy results

Outcome	Axitinib (N = 27)	Observation (N = 27)	Observation, after crossover (N = 26)
6-month progression-free survival rate	“73% (52%–86%)”	“23% (9%–41%)”	“74% (51%–88%)”
Median progression-free survival, months	“10.8 (7.1–13.6)”	“2.8 (1.7–4.2)”	“14.5 (10.7–20.3)”
Hazard ratio for progression-free survival	“0.25 (0.14–0.48)”
Median overall survival, months	“NR (14.8–)”	“27.2 (20.2–32.8)”
Hazard ratio for overall survival	“0.60 (0.26–1.38)”
Overall response rate	“0.0 (0.0–12.8)”	“0.0 (0.0–12.8)”	“11.5 (2.5–30.2)”
Disease control rate	“100.0 (87.2–100.0)”	“51.9 (31.9–71.3)”	“92.3 (74.9–99.1)”
Median follow-up, months	“31.9”	“28.4”

Axitinib versus observation: trial design, eligibility, and response assessment

“This study was an investigator-initiated, randomized, open-labeled, prospective phase II trial.” (opens the source at this quote in a new tab)
“Patients that were 20 years of age or over with pathologically confirmed recurrent or metastatic ACC, which was not appropriate to curative treatment, were eligible if they had experienced disease progression within the 9 months prior to the study.” (opens the source at this quote in a new tab)
“Prior use of cytotoxic chemotherapy, other than antiangiogenic inhibitor treatment, was allowed.” (opens the source at this quote in a new tab)
“Once disease progression was confirmed, patients in the observation arm were crossed over to axitinib treatment.” (opens the source at this quote in a new tab)
“The primary endpoint was the 6-month progression-free survival (PFS) rate, as determined by the investigators in accordance with RECIST 1.1” (opens the source at this quote in a new tab)
“The response evaluations were conducted via RECIST 1.1 and performed every 8 weeks until cancer progression. Tumor assessment was conducted every 8 weeks for both groups.” (opens the source at this quote in a new tab)
“Efficacy analysis was performed on a per-protocol basis. Non-evaluable patients were excluded from the per-protocol analysis.” (opens the source at this quote in a new tab)

Axitinib in salivary gland carcinoma including ACC: single-center phase II trial

“This was a phase II, prospective, single-center, single arm trial with axitinib in patients with R/M SGCs not more amenable to curative options. One line of previous chemotherapy or TKI was allowed in patients with r/m non-ACC but not in ACC ones. Clinical or radiological progression of disease within 6 months of enrolment was required for inclusion.” (opens the source at this quote in a new tab)
“Primary end point was the assessment of activity of axitinib in terms of objective response rate (ORR) according to RECIST v1.1.” (opens the source at this quote in a new tab)
“Axitinib was administered at 5 mg twice a day (bid) (starting dose); in case of no AEs above grade 2 for a consecutive 2-week periods, the dose could be increased to 7 mg bid and further to 10 mg bid using the same criteria until tumor progression, unacceptable toxicity, or other criteria for discontinuation was met. Radiological assessments were performed at baseline and every 8 weeks.” (opens the source at this quote in a new tab)
“Twenty-six patients (50% were male; 6 ACC, 20 non-ACC) were treated. Response rate was 8% (2 partial responses), 13 stable disease (>6 months in 7 patients) and 11 disease progression. Median progression-free survival and overall survival were 5.5 and 26.2 months, respectively.” (opens the source at this quote in a new tab)

Sorafenib: phase II trial design, eligibility, and response assessment

“Any number of prior therapies were allowed, including chemotherapy, other molecularly targeted agents, radiofrequency ablation, and radiotherapy.” (opens the source at this quote in a new tab)
“The study treatment was delivered as an out-patient and consisted of sorafenib 400 mg twice daily, taken orally on a continuous schedule.” (opens the source at this quote in a new tab)
“Response to treatment was evaluated radiologically, using MRI/CT for locally recurrent disease and/or CT for sites of metastatic disease at intervals of 4 months or on clinical suspicion of progressive disease, and classified according to RECIST 1.1 criteria.” (opens the source at this quote in a new tab)
“The primary purpose of this study was to determine PFS at 12 months in sorafenib-treated patients with advanced salivary ACC. Secondary purposes were to measure response rate (complete and partial responses), time to progression (TTP), OS, and to characterize the toxicity profile of sorafenib in this patient group.” (opens the source at this quote in a new tab)

Sorafenib: response and survival in advanced ACC of the head and neck

“Twenty-three patients, median age 51 years, were recruited from 2009 to 2011.” (opens the source at this quote in a new tab)
“Median PFS and OS were 11.3 (95% confidence interval [CI], 8.9–13.7) and 19.6 (CI, 12.4–26.8) months, respectively” (opens the source at this quote in a new tab)
“Radiological response was not evaluable in 4 patients (17%) because of early discontinuation of sorafenib” (opens the source at this quote in a new tab)
“2 patients (11%) demonstrated a partial response (PR), 13 (68%) had stable disease, and 4 (21%) had progressive disease” (opens the source at this quote in a new tab)
“Both patients with PR showed reduction in disease at the primary site with stable disease elsewhere. Stable disease at 6 and 12 months was seen in 68% and 42% of patients, respectively.” (opens the source at this quote in a new tab)

Lenvatinib in real-world use: eligibility, starting dose, treatment duration, and clinical benefit

“To be considered for the study, patients should be ≥ 18 years of age, have ECOG Performance Status (PS) 0–2, and histological diagnosis of ACC, with treatment using lenvatinib. Any prior line of systemic therapies, except lenvatinib, was allowed. Radiological images were internally reviewed with local radiologists, applying RECIST criteria.” (opens the source at this quote in a new tab)
“From August 2020 to January 2022, 51 patients were included across 17 Italian sites. The median follow-up was 10.8 months (95% CI 9.1–13.3). All patients had a progressive disease, either clinical or radiological, at the time of lenvatinib initiation.” (opens the source at this quote in a new tab)
“All patients received at least one dose of lenvatinib. Sixteen patients (31.37%) started treatment at the full dose of 24 mg daily, while all the others began with a reduced dose (Table 2). Among the 10 patients (19.6%) who started with a lenvatinib dose of 10 mg or less, 4 patients (40%) increased the dose by 4 mg during treatment. The median duration of therapy was 5.9 months (range 0.7–17.8+).” (opens the source at this quote in a new tab)
“Stable disease lasting longer than 6 months was observed in 16 subjects (34.8%). When these cases were combined with the 10 responders, a clinical benefit was observed in 56.5% of cases.” (opens the source at this quote in a new tab)

Lenvatinib phase II trial: enrollment, response detail, and clinical benefit rate

“The current study was a prospective, single-arm, phase 2 trial performed at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and examining lenvatinib at a dose of 24 mg daily administered to patients with R/M ACC until disease progression or unacceptable toxicity occurred.” (opens the source at this quote in a new tab)
“From June 2015 to August 2017, a total of 28 patients were enrolled.” (opens the source at this quote in a new tab)
“Approximately 21% of patients (6 of 28 patients) had extensive local disease with skull base involvement and/or disease close to the internal carotid artery. Two patients died before first disease reassessment due to rapid disease progression and were replaced by 2 other evaluable patients.” (opens the source at this quote in a new tab)
“Among the 26 patients who were evaluable for response, 3 patients achieved a partial response (11.5%), 20 patients had stable disease, and 3 patients experienced disease progression as their best response. No complete response was observed. Target lesion shrinkage between 23% and 28% was observed in 4 of 20 patients with stable disease (see Supporting Fig. 1). Clinical benefit (partial response and stable disease maintained for ≥6 months) was reported in 17 patients (65.4%). The median PFS and duration of response were 9.1 months (95% CI, 5.5-13.8 months) and 3.1 months (range, 1.8-30.7 months), respectively.” (opens the source at this quote in a new tab)
“The median time to response according to Response Evaluation Criteria in Solid Tumours (RECIST) was 5.4 months (range, 1.7-11 months).” (opens the source at this quote in a new tab)