Summary: limitations of local, surveillance, and systemic approaches in R/M ACC

No systemic therapy is approved by the FDA for recurrent or metastatic ACC, and the ESMO-EURACAN guideline states that no systemic treatment has been shown to improve overall survival. Guideline-endorsed systemic options (multitargeted VEGFR tyrosine kinase inhibitors and platinum-based chemotherapy) are supported by single-arm phase II trials and one randomized phase II trial, and NCCN lists lenvatinib and axitinib plus avelumab as category 2B options.

Objective responses are infrequent. A meta-analysis of 17 VEGFR inhibitor studies (560 participants) reported a pooled objective response rate of 6%, with stable disease as the most frequent best response (82%). Response rates were 15.6% with lenvatinib (32 evaluable participants), 11.5% in a second lenvatinib phase II trial (26 evaluable participants), 21.7% in a real-world lenvatinib cohort (46 evaluable participants), 9.1% with axitinib in ACC (33 participants), 8% with axitinib in a single-center trial in salivary gland carcinomas (26 participants), 0.0% with axitinib in the randomized trial versus observation, 11% with sorafenib (19 evaluable participants), 18% with axitinib plus avelumab (28 evaluable participants), and 9.7% by blinded independent review with rivoceranib (72 evaluable participants). Progression-free survival captures activity that the response rate does not: in the randomized axitinib trial the 6-month PFS rate was 73.0% with axitinib and 23.0% with observation and the disease control rate was 100.0% versus 51.9%, and median PFS was 10.8 versus 2.8 months (hazard ratio 0.25), yet neither arm produced a response and there was no statistically significant overall survival difference (P = 0.226), which the investigators attribute in part to crossover. Cytotoxic chemotherapy produced objective responses in 22 of 163 participants (16%) across single-agent studies and 25% with CAP, with greater toxicity for combinations.

Tolerability limits treatment duration and dose intensity. In the lenvatinib phase II trial reported by Tchekmedyian, 23 of 32 participants required dose modification and 18 of 32 discontinued for drug-related issues; in the Italian lenvatinib phase II trial, 96% had a treatment-related adverse event, grade 3 events occurred in approximately half of participants, dose reductions were required in 24 of 28, and 88% of first reductions occurred within 12 weeks. In the real-world lenvatinib cohort, every participant had a treatment-related adverse event, the most frequent grade 3 or higher events were hypertension (25.49%), stomatitis (17.65%), and fatigue (15.69%), 32 of 51 participants (63.6%) required a dose reduction, one fatal drug-related bleeding occurred, and only 16 of 51 (31.37%) started at the full 24 mg dose. With sorafenib, 13 of 23 participants (57%) had grade 3 toxicity and 74% required a dose reduction, and the investigators concluded that single-agent sorafenib could not be recommended for further evaluation. With axitinib in salivary gland carcinomas, all participants had a drug-related adverse event, grade 3 or higher events occurred in 12 of 26 (46%), median dose intensity was 59%, and the trial did not meet its primary endpoint. With rivoceranib, 70.0% had grade 3 or higher treatment-related adverse events and 85.0% required dose modification. The pooled dose reduction rate for VEGFR inhibitors was 59%. Because participants with recurrent or metastatic ACC often have few symptoms and prolonged life expectancy, even grade 1 to 2 adverse events can reduce quality of life, which deteriorated for fatigue and dry mouth by 6 months on lenvatinib.

Outcomes are worse in the aggressive subgroup targeted by emiltatug ledadotin. With axitinib plus avelumab, median PFS was 1.8 months in ACC-I versus 11.4 months in ACC-II, and in a real-world cohort ACC-I was associated with worse outcomes across pooled systemic treatment categories (HR 3.06). NOTCH inhibitors in NOTCH-activated disease (86% solid histology) produced a median PFS of 4.2 months. Pulmonary metastasis-directed local therapy did not increase overall survival in unselected patients, and active surveillance is recommended mainly for asymptomatic, low-burden, lung-only disease, which is less typical of solid or high-grade transformed ACC. Subtype-specific comparator evidence is otherwise scarce: the randomized axitinib trial did not capture detailed information on pathologic subtype, and the claims-based comparison of ACC-I and ACC-II by treatment type had limited sample sizes per treatment cohort and no information on clinical response.

No approved systemic therapy for R/M ACC

“There is no systemic therapy for recurrent or metastatic adenoid cystic carcinoma (ACC) approved by the US Food and Drug Administration.” (opens the source at this quote in a new tab)
“The rate of grade 3 or higher adverse events was 53% (95% CI, 42%-64%; I2 = 81%) and of DRR was 59% (95% CI, 40%-76%). Most patients (57%; 95% CI, 44%-70%; I2 = 83%) continued therapy until PD; 21% (95% CI, 15%-28%; I2 = 62%) of patients suspended therapy for toxic effects.” (opens the source at this quote in a new tab)

“No systemic treatments are approved for use in R/M ACC in the United States or Europe. Cytotoxic chemotherapy typically results in low response rates and is often reserved for symptomatic or rapidly progressive disease (PD; refs. 1, 4).” (opens the source at this quote in a new tab)

Toxicity and quality of life with lenvatinib

“Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1).” (opens the source at this quote in a new tab)

“Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events).” (opens the source at this quote in a new tab)
“The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth.” (opens the source at this quote in a new tab)

Toxicity with rivoceranib

“Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity.” (opens the source at this quote in a new tab)

Stable disease as the predominant benefit of VEGFR-TKIs

“Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.” (opens the source at this quote in a new tab)

Axitinib in salivary gland cancer: primary endpoint not met, toxicity, and dose intensity

“This trial did not meet its primary endpoint hence axitinib should not be considered for further investigations in SGCs.” (opens the source at this quote in a new tab)
“All patients had at least one drug related AE: stomatitis (69%), fatigue (58%), arterial hypertension (54%), diarrhea (50%), hypothyroidism (31%) and hand-foot syndrome (27%) were the most frequent. Grade ≥3 AEs” (opens the source at this quote in a new tab)
“were observed in 12 patients (46%): hypertension (31%) and weight loss (8%) were the most common TR AEs. Neither bleedings nor grade 5 AEs were observed.” (opens the source at this quote in a new tab)
“Median dose intensity was 59% (range 26%-100%).” (opens the source at this quote in a new tab)

Sorafenib: grade 3 toxicity, dose reductions, and trial conclusion

“The median duration of sorafenib treatment was 11.8 months. However, it was only reasonably well tolerated and 13 patients (57%) experienced grade 3 toxicity. There were 25 grade 3 events (Table 4).” (opens the source at this quote in a new tab)
“A dose reduction was required in 74% of patients (12 of 23 patients were reduced to 600 mg and 5 of 23 to 400 mg) and only 6 of 23 patients did not receive this.” (opens the source at this quote in a new tab)
“However, sorafenib 400 mg twice daily was associated with significant toxicity. When considered together with limited effectiveness, single agent sorafenib cannot be enthusiastically recommended for further evaluation.” (opens the source at this quote in a new tab)

Lenvatinib in real-world use: grade 3 or higher adverse events and dose reductions

“All patients were included in the safety analysis and experienced at least one TRAE of any grade (Table 4). The most common grade ≥ 3 TRAE were hypertension (25.49%), stomatitis (17.65%), and fatigue (15.69%). Thirty-two patients (63.6%) required at least one dose reduction due to adverse events. One fatal drug-related bleeding was reported after 6 months of lenvatinib treatment in a patient with lung metastases from a previous ACC of the right parotid.” (opens the source at this quote in a new tab)
“The rate of stomatitis > Grade 3 (17.65%) was unexpectedly higher than that reported in other studies” (opens the source at this quote in a new tab)

Lenvatinib phase II trial: dose reductions, serious adverse events, and discontinuation

“Nearly all patients (96%) experienced at least 1 treatment-related AE (see Supporting Table 2). The median duration of treatment for the study population was 9.1 months (range, 2.4-36.1 months). Grade 3 AEs (grading was performed according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events) occurred in approximately one-half of patients, whereas no grade 4 and grade 5 toxicities were observed.” (opens the source at this quote in a new tab)
“The starting dose of lenvatinib was 24 mg. Dose reductions were required for 24 patients. Four patients maintained the full dose for a median of 1.7 months (range, 1.0-2.8 months). The first dose reduction occurred within 12 weeks from the initiation of therapy in approximately 88% of patients (21 of 24 patients)” (opens the source at this quote in a new tab)
“The median time to the appearance of any SAE was 9.6 months (range, 0.4-29 months). Hypertension was the earliest reported SAE at 0.4 months.” (opens the source at this quote in a new tab)
“In 2 responding patients (see Supporting Fig. 2), tumor shrinkage was complicated by the formation of an oral fistula that required the placement of a gastrostomy tube.” (opens the source at this quote in a new tab)
“Disease progression was the main cause of treatment discontinuation, occurring in approximately 88% of patients. Conversely, 1 patient discontinued treatment for unsustainable toxicity despite dose reductions (grade 2 asthenia and weight loss).” (opens the source at this quote in a new tab)

Tolerability of multikinase inhibitors in a population with few symptoms

“These patients generally experience few symptoms, and have a prolonged life expectancy despite the presence of R/M disease. In this scenario, there is major concern regarding the use of MKIs that may commonly induce side effects in an otherwise poorly symptomatic population. Within this context, even low-grade (grade 1 to grade 2) side effects might cause patients’ QOL to deteriorate.” (opens the source at this quote in a new tab)

Axitinib: adverse events, dose reductions, and discontinuation compared with lenvatinib

“The most frequently reported adverse event for the axitinib arm was grade 1 or 2 stomatitis (43.3%), with anorexia (33.3%) and proteinuria (33.3%) the next-most frequently reported AEs. The most frequent grade 3 AE was hypertension (23.3%).” (opens the source at this quote in a new tab)
“Eight patients (6 in the axitinib arm, 2 after crossover to axitinib in the observation arm) required at least one dose reduction.” (opens the source at this quote in a new tab)
“The dose intensity was 76.2% in the axitinib arm and 76.6% in patients who crossed over to axitinib in the observation arm.” (opens the source at this quote in a new tab)
“the response rate was 15.6%, and the median PFS was 17.5 months. However, 62.5% of patients had at least one grade 3 or 4 toxicity, and 18 patients (54.5%) discontinued treatment due to AEs. In this study, there was no grade 4 toxicity at all. In addition, only 6 patients in the axitinib arm (20.0%) discontinued treatment due to AEs.” (opens the source at this quote in a new tab)

Emiltatug ledadotin (Emi-Le)

Limitations of current therapies