Key predictive factors for efficacy of axitinib in first-line
                    metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a
                    randomized, double-blind phase II study

Tomita, Yoshihiko; Fukasawa, Satoshi; Oya, Mototsugu; Uemura, Hirotsugu; Shinohara, Nobuo; Habuchi, Tomonori; Rini, Brian I.; Chen, Ying; Bair, Angel H.; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

doi:10.1093/jjco/hyw103

Cited by 21 publications

(30 citation statements)

References 31 publications

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“…Despite longer duration of axitinib treatment, the updated safety assessments did not reveal any new AE of significance in Japanese patients. As previously described, the nature of AE was similar between Japanese and non‐Japanese patients, with minor differences in incidence rates for some AE . The pharmacokinetics seemingly did not contribute to the differences in axitinib efficacy between Japanese and non‐Japanese because the range for the maximum observed plasma concentration as well as drug exposure at steady‐state generally overlapped between Japanese and non‐Japanese patients …”

Section: Discussionsupporting

confidence: 60%

“…The demographics and baseline characteristics of overall Japanese versus non‐Japanese patients are summarized in Table . The median age of Japanese patients was 5 years older than non‐Japanese patients, but Japanese patients had more favorable baseline prognosis, with ECOG PS 0, fewer metastases and smaller tumor size.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate whether axitinib is efficacious and safe in Japanese patients with metastatic RCC in the first‐line setting and, if so, whether Japanese patients achieve better efficacy outcomes than non‐Japanese patients, we conducted a subgroup analysis from this multinational, randomized phase II trial. The analysis indicated that axitinib is effective, with median PFS exceeding 2 years, and is well tolerated in treatment‐naïve Japanese patients with metastatic RCC . The objective response rate (95% CI) in Japanese patients was 66% (50–80) compared with 44% (36–52) in non‐Japanese patients, providing further evidence for more favorable clinical outcomes in axitinib‐treated Japanese patients.…”

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confidence: 89%

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Overall survival of first‐line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study

et al. 2017

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Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression‐free survival of 27.6 months in treatment‐naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and safety in 44 Japanese patients and compared the results with 169 non‐Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first‐line metastatic RCC were explored in all patients using a Cox proportional hazard model. With median follow‐up of 33 months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months–not estimable), whereas 107 of 169 (63%) non‐Japanese patients had died and median OS was 33.9 months (95% CI, 28.9–42.7). Estimated 1‐year, 2‐year and 3‐year survival probability (95% CI) was 86.4% (76.2–96.5), 75.0% (62.2–87.8) and 68.2% (54.4–81.9), respectively, in Japanese patients, and was higher than that in non‐Japanese patients (75.1% [68.4–81.8], 62.1% [54.5–69.7] and 47.2% [39.3–55.1], respectively). The updated safety analysis did not reveal any new adverse events of concern among Japanese or non‐Japanese patients. The multivariate analysis identified that lower baseline Eastern Cooperative Oncology Group performance status, lower baseline tumor burden, and longer time from histopathological diagnosis to treatment were significant positive predictors of OS. The current analysis confirmed the clinical activity of axitinib in treatment‐naïve Japanese patients with metastatic RCC, with an acceptable toxicity profile.

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

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confidence: 89%

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Overall survival of first‐line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study

et al. 2017

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“…Thyroid disorders showed the largest difference in frequency between Japanese patients and the overall population (51.5% vs 24.7%), which caused the higher frequency of total immune‐related adverse events observed in Japanese patients. However, it was previously reported that the incidence of hypothyroidism with axitinib treatment alone was also higher in Japanese patients than the overall population in the studies of single‐agent axitinib in patients with advanced RCC . The trend of higher frequency of hypothyroidism in Japanese patients compared to the overall population was observed with other VEGFR inhibitors, such as sorafenib and regorafenib .…”

Section: Discussionmentioning

confidence: 96%

“…Second‐line treatment with axitinib was well tolerated and showed antitumor activity in Japanese patients with metastatic RCC and was approved for second‐line treatment of advanced RCC in Japan in June 2012. Axitinib has also shown antitumor activity and a manageable safety profile for the treatment of patients with metastatic RCC in the first‐line setting in randomized studies, including in Japanese patients …”

Section: Introductionmentioning

confidence: 99%

Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101

et al. 2020

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The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment‐naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression‐free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD‐L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD‐L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD‐L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD‐L1+ tumors and irrespective of PD‐L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD‐L1 expression. Common treatment‐emergent adverse events (all grade; grade ≥3) in each arm were hand‐foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment‐naive Japanese patients with advanced RCC, which is consistent with results in the overall population.

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Pharmacokinetics of Neoadjuvant Axitinib Influenced the Efficacy in Patients With Advanced Renal Cell Carcinoma

Yamamoto

Otori

Inoue

et al. 2019

The Journal of Clinical Pharma

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Although axitinib shows a good objective response rate and acceptable tolerability for advanced renal cell carcinoma, substantial differences in drug concentrations among individuals have hampered the reliable administration of the drug in a neoadjuvant setting. This study aimed to evaluate the relationship between axitinib pharmacokinetics and clinical efficacy in patients with advanced renal cell carcinoma treated in a neoadjuvant setting. We retrospectively reviewed 16 patients who underwent neoadjuvant axitinib treatment from prospective phase 2 study cohorts treated with axitinib and assessed whether the drug concentration was associated with clinical efficacy for primary tumors of advanced metastatic/oligometastatic clear cell renal cell carcinoma. Axitinib was administered orally at a starting dose of 5 mg twice daily for 2 months in principle before the operation, and the axitinib pharmacokinetics were examined. Best response, reduction rate, adverse events (AEs), and surgical complication were assessed. Four patients (25.0%) showed a partial response, and 12 (75.0%) had stable disease, with a mean reduction rate of 22.8%. No progressive disease was noted, and 9 of the 16 patinets (56.3%) showed downstaging. The trough level of axitinib significantly correlated with the objective response rate (P = .0052) and best tumor reduction (P = .0128). All AEs could be safely managed until termination of the dosing period. With respect to perioperative complications, grade 2 anemia was observed. Neoadjuvant axitinib treatment showed acceptable antitumor activity and safety profile for advanced renal cell carcinoma. The pharmacokinetics of neoadjuvant axitinib influenced the efficacy in patients with advanced renal cell carcinoma.

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Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a randomized, double-blind phase II study

Abstract: Axitinib demonstrated clinical activity and safety in treatment-naïve Japanese patients with metastatic renal cell carcinoma. Multivariate analyses identified potential predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma.

Cited by 21 publications

References 31 publications

Overall survival of first‐line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study

Overall survival of first‐line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study

Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101

Pharmacokinetics of Neoadjuvant Axitinib Influenced the Efficacy in Patients With Advanced Renal Cell Carcinoma

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