Our study established that intravenous copanlisib combined with weekly intravenous cetuximab could not be safely administered to patients with recurrent and/or metastatic HNSCC without a premedication with metformin because of hyperglycemia. Although a premedication with metformin would have allowed to re-escalate, the sponsor decided to stop the study given the poor tolerance and limited efficacy. Therefore, both the maximum tolerated dose and the recommended phase 2 dose of the combination could not be established.
The most common copanlisib-related AEs were hyperglycemia and hypertension. The safety profile of cetuximab did not seem to be impacted by the addition of copanlisib, with common class-effect toxicities including rash and hypomagnesemia.
The overall incidence of all-grade and grade 3 hyperglycemia were 64% and 36% respectively. In clinical trials evaluating single-agent copanlisib in lymphoma patients at the dose of 60 mg, the overall incidences of all-grade and grade \(\ge\) 3 hyperglycemia were slightly lower, being 50% and 40%, respectively [17, 19]. The higher incidence of grade 3 hyperglycemia reported in our study might be related to our HNSCC patient population. Due to cancer-or treatment-related dysphagia, most patients were fed with means increasing the risk of hyperglycemia, including the use of a gastrostomy, parenteral nutrition, and oral nutritional supplements. In addition, most of patients were receiving corticosteroids that is known to increase glycemia. Hyperglycemia is a recognized on-target effect of p110α inhibition, given that p110α is a critical lipid kinase required for insulin signaling in two key cell types, including adipocytes and myotubes [20, 21].
The incidences of all-grade (46%) and grade 3 (36%) hypertension were also higher than reported in clinical trials evaluating single-agent copanlisib at the dose of 60 mg [17, 19]. These differences can be explained by the high rate of patients with hypertension at baseline in our study (27%). Furthermore, HNSCC patients often suffer from cardiovascular comorbidities due to tobacco and alcohol consumption . Gastrointestinal toxicities remained low relative to orally administered PI3K inhibitors [23, 24], presumably due to the intravenous route of administration, and the absence of a first-pass metabolism. In addition, a lower incidence of diarrhea (18%) and transaminases increase (9%) was observed in our study as compared with those reported in single-agent studies of copanlisib at the dose of 60 mg [17, 19].
Pharmacokinetics parameters of copanlisib combined with cetuximab were consistent with those reported for weight-based dosing copanlisib monotherapy , including a short Tmax and a long t1/2. Copanlisib had a large tissue diffusion with similar Cmax on Days 1 and 15. Given the lack of significant accumulation, our results suggest no pharmacokinetics interaction between copanlisib and cetuximab. This was expected since the metabolism of copanlisib is mediated via CYP3A4/5 (> 90%) and to a minor extent via CYP1A1 (< 10%) , and cetuximab is a monoclonal antibody that is degraded by macrophages without any liver metabolism. Copanlisib pharmacokinetics was dose proportional.
Four out of eight evaluable patients achieved disease stabilization according to RECIST1.1, but no objective responses were observed. The limited efficacy observed in our study might be explained by several factors. First, none of the patients were exposed to the recommended phase II dose of copanlisib as single agent. Given that all patients had progressed on cetuximab before, it is unlikely that a suboptimal dose of copanlisib might have been able to produce antitumor activity in combination with cetuximab. Second, our patient population was heavily pretreated with a poor prognosis as exemplified by the fact that three patients died within two months following their entry in the study. Despite the suboptimal treatment received, the observed median overall survival (6.01 months) and median progression-free survival (2.66 months) were in line with the results obtained in a randomized phase II clinical trial evaluating PX-866, an irreversible oral PI3K inhibitor, in combination with cetuximab in a similar patient population .
In summary, copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients. The use of a premedication with metformin might have allowed to increase the dose of copanlisib to a potentially effective dose. The inclusion of a larger patient population would have allowed to evaluate a potential differential effect between patients with tumors harboring a PIK3CA or PTEN alteration versus the others.