2018-19 Section 7-Neoplastic and Inflammatory Diseases of the Head and Neck eBook

Immunotherapy for recurrent/metastatic head and neck cancer Alfieri et al.

(vs. 19.7 and 8.3% in the SOC arm, respectively). On January 2016, this trial was amended to permit cross-over to nivolumab for patients on SOC. It is quite interesting to note that progression-free sur- vival (PFS) curves were similar at 3 months for both arms (2.0 vs. 2.3 months; P ¼ 0.82) but there was a nonsignificant trend in favor to nivolumab thereaf- ter. This means that patients treated with nivolu- mab are more likely to benefit in terms of survival outcomes. The objective response rate (ORR) of nivolumab was significantly better than SOC (13.3 vs. 5.8%, respectively), with more than half of responders seen at first evaluation [10]. The median duration of response was long (12.5 months; range, 5–24 þ ) [10]. To date, there were no established factors to predict response, even if a higher PD-L1 expression seems to be related with response. Sur- vival was slightly worse in those who had been previously treated with cetuximab than in cetuxi- mab-naive patients (7.1 vs. 8.2 months, respec- tively) [11]. This could be due to the PD-L1 down- regulation mediated by EGFR-inhibition. In CheckMate-141 study, 42% of patients enrolled in nivolumab armwere on immunotherapy beyond disease progression (programmed death) according to investigator’s judgement [12]. All indi- viduals of this subgroup were in good performance status (ECOG PS 0–1), with the majority of them (61.3%) slowly progressive with increase in only one target lesion. Twenty-four percent of patients expe- rienced tumor reduction higher than 20% even if only 3 patients had partial response according to RECIST 1.1 (Response evaluation criteria in solid tumors). In CheckMate-141, no pseudo-progression was described thus confirming the intrinsic differ- ence between HNSCC and melanoma, where 6.7– 12% of patients responded despite PD at their first evaluation [13]. This means that it is essential to change therapy if we have no clinical response, especially if performance status and disease are extensively and rapidly worsening. With regards to safety, nivolumab had lower percentage of grade 3–4 (G3–4) adverse events in respect to SOC (13.1 vs. 35%, respectively) [9 && ]. Fatigue, nausea, rash, appetite loss, pruritus were the most common adverse events in the nivolumab arm. Adverse events of special interest afflicted over- all skin and endocrine system while pneumonia was lower (2.1%) in nivolumab group. In CheckMate- 141, a quality of life (QoL) evaluation was planned throughout three EORTC questionnaires at baseline, after 2 months and every 6 weeks thereafter: QoL Questionnaire-Core 30 (QLQ-C30), EORTCHead and Neck Cancer-specific Module (EORTCQLQ-H&N35), and Three-level European Quality of life-5 Dimen- sions (EQ-5D). At baseline, QoL was similar in both

death-ligand 1) axis (nivolumab, pembrolizumab, atezolizumab, durvalumab). This target plays a crit- ical role in the antitumor immune system response. Normally, PD-1 is expressed on tumor cells surface and PD-L1 on the immune cells (stromal, lympho- cytes, etc.) and the interaction between them leads to inhibition of physiological antitumor immune response [8]. All drugs binding PD-1 or PD-L1 are able to turn-off the inhibitory signal from the tumor, thus stimulating the immune system. NIVOLUMAB Nivolumab, an anti-PD1 agent, has already been approved by the Food and Drug Administration (FDA) on November 2016 and the European Medi- cines Agency (EMA) on April 2017, as second-line therapy for platinum-refractory (disease progression within 6 months after last dose of platinum) R/M HNSCC. The pivotal study for nivolumab was CheckMate-141 [9 && ]. This trial enrolled 361 R/M HNSCC to receive (2 : 1) nivolumab (3mg/kg every 2 weeks) or standard of care (SOC), such as Doce- taxel, Methotrexate, or cetuximab, selected accord- ing to the investigator’s choice. The majority of patients had oral cavity cancer (48.5%) and at least one previous line therapy administered for advanced disease (47.4%). This study met its pri- mary endpoint as patients treated with nivolumab had better overall survival (OS) than those with SOC (7.5 vs. 5.1 months, respectively; P ¼ 0.01). This advantage in OS was more evident in HPV-positive subgroup. Moreover, OS at 12 and 18 months was 34% and 21.5% for patients treated with nivolumab KEY POINTS After cetuximab, anti-PD1/PD-L1 agents were the first systemic drugs to demonstrate significant activity and efficacy in the second-line treatment of platinum- refractory R/M HNSCC. Anti-PD1/PD-L1 agents resulted better tolerated than chemotherapy. In HNSCC, immunotherapy is changing the state of the art of R/M HNSCC. Ongoing studies will clarify the best use of immunotherapy, if alone or in combination with conventional/targeted/other immune agents, and in which disease setting. The identification of biomarkers as predictive of response to anti-PD1/PD-L1 is a key point to tailor immunotherapies on each patient thus exploiting these agents at the best.

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