Non-Superiority of Weekly Dose-Dense Chemotherapy Versus SOC Shown in Epithelial Ovarian Cancer

Andrew Clamp, BMBCh

Patients with epithelial ovarian cancer treated with weekly dose-dense chemotherapy in the ICON8 clinical trial experienced similar progression-free survival (PFS) and overall survival (OS) as patients treated with the standard-of-care (SOC), demonstrating that weekly dose-dense chemotherapy is not superior of SOC in this population, according to a presentation at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.¹

Weekly dose-dense chemotherapy is not superior to standard 3 weekly chemotherapy for patients with epithelial ovarian cancer when it comes to progression-free survival (PFS) and overall survival (OS), though the regimen is safe and effective, according to results from the ICON8 study presented at the ESMO Virtual Congress 2020.1

“[For] the most of the last 3 decades, platinum paclitaxel doublet chemotherapy administered on a once every 3 week schedule for 6 to 8 cycles has been cornerstone in the first-line modality management of epithelial ovarian cancer,” said chief investigator Andrew Clamp, BMBCh, senior lecturer and honorary consultant in medical oncology at the Christie NHS Foundation Trust.

ICON8 included 1566 patients with epithelial ovarian cancer who had FIGO stage IcG3-IV disease. Participants were randomized 1:1:1 to 3 arms:

• Arm 1, standard chemotherapy, q3w carboplatin AUC5/6 plus q3w paclitaxel 175 mg/m² (n=522)
• Arm 2, weekly paclitaxel (q3w carboplatin AUC5/6 plus q1w paclitaxel 80mg/m2 (n=523)
• Arm 3, weekly carboplatin-paclitaxel (q1w carboplatin AUC2 plus q1w paclitaxel 80 mg/m² (n=521)

“There’s a strong rationale for the evaluation of weekly dose paclitaxel after settling in to the first line of treatment,” Clamp said, citing preclinical animal evidence of metronomic taxane treatment could improve drug delivery, increase tumor cell apoptosis, and reduce angiogenesis.

Baseline characteristics were well balanced among the arms. The median age of study participant was 62; 72% had serous histology; 10.5% were stage Ic-IIa; 18% were stage IIa-IIIb; and 71% were stage IIIc-IV. Half (50%) of patients planned delated primary surgery (DPS), while slightly less (48%) had immediate primary surgery (IPS). Two percent of patients were inoperable.

As of October 1, 2019, median OS was 47.4, 54.1, and 53.4 months in arms 1, 2, and 3, respectively. There were 319 deaths in arm 1 (61%), 300 deaths in arm 2 (57%), and 304 deaths in arm 3 (58%). There was no significant improvement in OS comparing arm 2 versus arm 1 (97.5% CI, 0.74-1.06; p=.14, HR =.88); arm 3 versus arm 1 (97.5% CI, 0.76-1.09; p=0.27, HR=0.91).

Median time to progression was 25, 25.5, and 25.9 months in arms 1, 2, and 3, respectively, again showing no statistically significant difference (arm 2 versus arm 1 p=0.37; arm 3 versus arm 1 p=0.48).

The toxicity profile of the weekly regimen was previously presented at the ESMO annual meeting in 2017, and Clamp said that there were no changes in adverse events.

“The two weekly treatment arms were associated with an increased incidence of any grade 3 or 4 events during treatment, but this was predominantly driven by uncomplicated growth [grade] 3 or 4 neutropenia,” Clamp said. “Reassuringly, incidence of febrile neutropenia was low in all 3 treatment arms, and we did not see any increase of grade 2 or more sensory neuropathy in the 2 weekly dose-dense paclitaxel-containing regimen.”

Ultimately, Clamp explained that since the dose-dense regimen did not show improved survival results, weekly paclitaxel can remain standard of care for this patient population, though more research is needed.

“Other further hypothesis-generating analyses are underway in our DPS cohort to determine if there is a subgroup of patients who may benefit with the more dense approach,” Clamp said.

_Reference

_{Clamp AR, James EC, McNeish I, et. al. ICON8: overall survival results in a GCIC phase III randomized controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment. Presented at: ESMO Virtual Congress 2020, Sept. 19-21, 2020. Accessed Sept. 21, 2020.}