Amrubicin

From discovery to approval

1. 1988 · Earliest report found

   The earliest reports found are Japanese papers of 1988 and 1989 on SM-5887, described in English abstracts as a new, totally synthetic anthracycline or 9-aminoanthracycline derivative; one is a 1988 phase I study. A 1999 paper identifies amrubicin hydrochloride as the 9-aminoanthracycline SM-5887.^{[2][3][4][5][6][7]}

2. No approval is recorded on this site.

How it works

Trial reports describe it as a synthetic anthracycline and potent topoisomerase II inhibitor. In mice its 13-hydroxy metabolite, amrubicinol, was 10 to 100 times more cytotoxic than amrubicin and reached higher tumour levels than doxorubicin reached in sensitive tumours.^[1]

Where it came from and why

No source read states why amrubicin was made. Horita's 2016 meta-analysis calls it a synthetic anthracycline with a structure similar to doxorubicin, and the phase 3 trial report calls it a third-generation anthracycline.

Cancers

• Small-cell lung cancer, relapsed

  A 2016 meta-analysis of 803 patients states that amrubicin is permitted for relapsed small-cell lung cancer only in Japan (its full text says it was approved there in 2002 and, as of 2015, only there).^[6]

• Small-cell lung cancer, second line, phase 2

  In 75 patients with platinum-refractory small-cell lung cancer, the overall response rate was 21.3% (95% CI 12.7% to 32.3%) with a median overall survival of 6.0 months.^[1]

• Small-cell lung cancer, second line, phase 3

  In a randomised trial of 637 patients against topotecan, median overall survival was 7.5 months with amrubicin and 7.8 months with topotecan (hazard ratio 0.880, p = .170), and the authors concluded that amrubicin did not improve survival.^[7]

Worth knowing

• In the phase 3 trial, patients with refractory disease had median overall survival of 6.2 months with amrubicin and 5.7 months with topotecan (hazard ratio 0.77, p = .047), and the overall response rate was 31.1% versus 16.9%.^[7]
• A 2016 meta-analysis reports grade 3 or 4 neutropenia in 70% of patients and febrile neutropenia in 12% across nine prospective studies.^[6]
• The phase 2 study found no decrease in mean left ventricular ejection fraction at cumulative doses exceeding 750 mg/m2, and the authors note that long-term effects on the heart are unknown.^[1]

References

1. Ettinger DS, Jotte R, Lorigan P, Gupta V, Garbo L, Alemany C, et al. Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer. J Clin Oncol. 2010;28(15):2598-603. PubMedDOI
2. Inoue K, Ogawa M, Horikoshi N, Mukaiyama T, Itoh Y, Imajoh K, et al. [Phase I study of SM-5887, a new anthracycline derivative]. Gan To Kagaku Ryoho. 1988;15(5):1771-6. PubMed
3. Morisada S, Yanagi Y, Noguchi T, Kashiwazaki Y, Fukui M. Antitumor activities of a novel 9-aminoanthracycline (SM-5887) against mouse experimental tumors and human tumor xenografts. Jpn J Cancer Res. 1989;80(1):69-76. PubMedDOI
4. Noguchi T, Ichii S, Morisada S, Yamaoka T, Yanagi Y. [Evaluation of amrubicin with a 5 day administration schedule in a mouse model]. Gan To Kagaku Ryoho. 1999;26(9):1305-12. PubMed
5. Noguchi T, Ichii S, Morisada S, Yamaoka T, Yanagi Y. Tumor-selective distribution of an active metabolite of the 9-aminoanthracycline amrubicin. Jpn J Cancer Res. 1998;89(10):1061-6. PubMedDOI
6. Horita N, Yamamoto M, Sato T, Tsukahara T, Nagakura H, Tashiro K, et al. Amrubicin for relapsed small-cell lung cancer: a systematic review and meta-analysis of 803 patients. Sci Rep. 2016;6:18999. PubMedDOI
7. von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012-9. PubMedDOI