Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression

Objectives

Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors.

Patients and methods

We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR_12w). Pre-treatment plasma samples were required to assess T790M resistant mutation.

Results

A total of 33 patients were enrolled in the phase I–II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400 mg p.o., QD, on days 1–7 and 15–21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR_12w was 28% (IC95%: 18.0–37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43–8.45) and overall survival (OS) 10.3 months (95% CI: 2.4–18.1).

Conclusion

Full dose of continuous erlotinib with vorinostat 400 mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression.     

The Gut in Heart Failure: Current Knowledge and Novel Frontiers

Heart failure (HF) represents a major health problem affecting millions of people worldwide. In the latest years, many efforts have been made to search for more effective strategies to prevent and modify the course of this disease, but results are still not satisfying. HF represents a complex clinical syndrome involving many other systems, including the gastrointestinal system. Although the relationship between the gut and HF is far from being fully understood, based on recent evidence highlighting the putative role of the gastrointestinal system in different cardiovascular diseases, it is conceivable that the gut-heart link may represent the basis for novel therapeutic approaches in the HF context as well. This intricate interplay involving typical hemodynamic changes and their consequences on gut morphology, permeability, and function, sets the stage for alterations in microbiota composition and is able to impact mechanisms of HF through different routes such as bacterial translocation and metabolic pathways. Thus, the modulation of the gut microbiota through diet, probiotics, and fecal transplantation has been suggested as a potential therapeutic approach. More interestingly, another effect of alteration in microbiota composition reflects in the upregulation of cotransporters (NHE3) with consequent salt and fluid overload and worsening visceral congestion. Therefore, the inhibitors of this cotransporter may also represent a novel therapeutic frontier. By review of recent data on this topic, we describe the current state of the complex interplay between the gastrointestinal and cardiac systems in HF, and the relevance of this knowledge in seeking new therapeutic strategies.