Article
作者: Leventic, Miro ; Kumar, Ravi Rejnish ; Dolivet, Gilles ; Zulkiflee Abu Bakar, Mohd ; Hao, Sheng-Po ; Cipriano, John ; Chen, Mu-Kuan ; Iyer, Subramania ; Uglesic, Vedran ; Krasic, Dragan ; Piffko, Jozsef ; Horadugoda, Jayamini ; Lifirenko, Igor ; Wang, Chen-Chi ; Adi, Rachmiel ; Csoszi, Tibor ; Markovic, Dusan ; Leovic, Dinko ; Bilic, Mario ; Bankowska-Wozniak, Magdalena ; Ejadi, Samel ; Bondarenko, Igor ; Fijuth, Jacek ; Sukhina, Olena ; Kumar, Kosanam Subramanian Kirushna ; Remenar, Eva ; Stosic, Srboljub ; Talor, Eyal ; Ladanyi, Andrea ; Kulikov, Eugeny ; Vynnychenko, Ihor ; Milovanovic, Jovica ; Oliver, Christopher ; Paramonov, Viktor ; Karpenko, Andrey ; Chien, Chih-Yen ; Abeysinghe, Prasad ; Petroiu, Diana ; Zhukavets, Aliaksandr ; Shparyk, Yaroslav ; Djanic, Davorin ; Klatka, Janusz ; Lavin, Philip ; Attili, Suresh ; Hetnal, Marcin ; Zivic, Misko ; Tsai, Ming-Hsui ; Bentsion, Dmitry ; Timar, Jozsef ; Imamovic, Nazim ; Fang, Ku-Hao ; Ponomareva, Olga ; Spiric, Sanja ; Rajan, Philip ; Sobat, Hrvoje ; Masic, Tarik ; Agarwal, Sandeep ; Kisely, Mihaly ; Zolotukhin, Stanislav ; Jovic, Rajko ; Suslu, Nilda ; Dimitrijevic, Milovan ; Abdullah, Baharudin ; Murugaiyan, Nagarajan ; Tsai, Sen-Tien ; Feinmesser, Raphel ; Arora, Rajendra Singh ; Hill, Julian ; Kawecki, Andrzej ; Shewalkar, Balaji ; Dvorkin, Mikhail ; Chaukar, Devendra ; Bakhtalovskiy, Vladyslav ; Okla, Slawomir ; Nemeth, Zsolt ; Kiralj, Aleksandar ; Pontejos, Alfredo Quintin Y. ; Young, James Edward Massey ; Nagarkar, Rajnish Vasant ; Yunus, Mohd Razif Mohamad ; Vatanasapt, Patravoot ; Lou, Pei-Jen ; Karchmit, Evgeniya
The randomized controlled pivotal phase 3 study evaluated efficacy and safety of neoadjuvant complex biologic, Leukocyte Interleukin Injection (LI), administered for 3 consecutive weeks pre-surgery, in treatment naïve resectable locally advanced primary squamous cell carcinoma of oral cavity and soft palate. Randomization 3:1:3 to LI+/-CIZ (cyclophosphamide, indomethacin, and zinc)+SOC, or SOC (standard of care) alone. LI-treated patients received 400 IU (as interleukin-2 equivalent; 200 IU peritumorally, 200 IU perilymphatically) sequentially, daily 5 days/week for 3 weeks before surgery. All subjects were to receive SOC. Post-surgery, patients with low risk for recurrence were to receive radiotherapy, while those with high risk received concurrent chemoradiotherapy. Median follow-up was 56 months. There were 923 ITT (Intent-to-Treat) subjects (380 ITT low-risk and 467 ITT high-risk). Pre-surgery objective early response (45 objective early responders; 5 complete responses [CRs], 40 partial responses [PRs], confirmed by pathology at surgery. LI (+/− CIZ) had 8.5% objective early responders (45/529 ITT) and 16% objective early responders (34/212 ITT low-risk) vs. no reported SOC objective early responders (0/394 ITT). Objective early responders significantly lowered death rate to 22.2% (ITT LI-treated), 12.5% (ITT low-risk LI + CIZ + SOC), while the ITT low-risk SOC death rate was 48.7%. Thus, objective early response impacted overall survival (OS); proportional hazard ratios were 0.348 (95% CI: 0.152–0.801) for ITT low-risk LI-treated, 0.246 (95% CI: 0.077–0.787) for ITT low-risk LI + CIZ + SOC. ITT low-risk LI + CIZ + SOC demonstrated significant OS advantage vs. ITT low-risk SOC (unstratified log-rank p = 0.048; Cox hazard ratio = 0.68; 95% CI: 0.48–0.95, Wald p = 0.024 [controlling for tumor stage, tumor location, and geographic region]). Absolute OS advantage increased over time for ITT low-risk (LI + CIZ + SOC)-treated vs. ITT low-risk SOC: reaching 14.1% (62.7% vs. 48.6%) at 60 months, with 46.5 months median OS advantage (101.7 months vs. 55.2 months), respectively. Quality of life benefit for complete responders sustained for >3 years post LI treatment. Percent treatment-emergent adverse events were comparable among all treated groups. No excess safety issues were reported for LI over SOC alone post-surgery. NCT01265849, EUDRA:2010-019952-35.