Pembrolizumab: living up to expectations

Abstract

Novel treatment strategies for T-PLL are urgently needed; candidate agents in clinical development for T-PLL include anti-BCL2 (alone 9 or in combination with ibrutinib [NCT03873493]), JAK/STAT pathway inhibitors (eg, combined tofacitinib and ruxolitinib, 10 or itacitinib [NCT03989466]), and anti-histone deacetylase (eg, romidepsin [NCT02512497]). In this scenario, the availability of robust diagnostic criteria, well-established indications for treatment, and homogeneous responses represent essential tools for investigating these novel therapies. Furthermore, the systematic investigation of biological features associated with disease progression may lead to the identification of molecular targets for the development of novel therapeutic agents. Future investigations are needed to validate these criteria and to identify baseline characteristics and longitudinal indicators associated with better long-term outcomes. Hopefully, this will also lead to the identification of meaningful clinical end points that may help assess the possible impacts of novel treatments. Indeed, we need to understand whether complete remission is required for long-term survival, or if even partial remission could result in satisfactory progression-free survival, especially in the era of novel, continuously given, target therapies. In contrast, if complete remission is the initial treatment goal, we will need to understand the meaning of minimal residual disease and its role in driving therapeutic interventions for subsequent maintenance or consolidation treatments. Of course this work from the TPLL-ISG is not the end of the story, but rather a starting point that paves the way for future clinical investigations that will improve the treatment of patients with T-PLL.

Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

“…The Phase I/IIa dose-escalation clinical trial NCT04101357 is assessing the efficacy, pharmacodynamics, pharmacokinetics and safety of BNT411, a novel TLR7 agonist, either given as a monotherapy in individuals affected by advanced solid tumors or administered in combination with the PD-L1-targeted ICB atezolizumab, 3 , 117 - 119 carboplatin and etoposide 120 , 121 in patients with chemotherapy-naïve extensive-stage small cell lung cancer (ES-SCLC). The synthetic TLR7 agonist DSP-0509 is being investigated for pharmacokinetic profile, tolerability, and safety upon intravenous administration as monotherapy or combined with pembrolizumab, 122 - 124 in adults with advanced solid malignancies (NCT03416335). Similar approaches under clinical testing involve the hitherto experimental PD-1-targeting agent spartalizumab (also known as PDR001) 125 - 128 and the TLR7 agonistic benzonapthyridine LHC165, 92 (NCT03301896), the PD-1-specific ICB nivolumab and the mixed TLR7/TLR8 agonist NKTR-262, 129 (NCT03435640), as well as nivolumab and motolimod (NCT04272333, NCT03906526).…”

Trial watch: IDO inhibitors in cancer therapy

“…Along similar lines, the remaining clinical trials that involve epacadostat assess safety and preliminary efficacy of the IDO1 inhibitor combined with pembrolizumab (and other immunotherapeutic regimens). 173 – 175 In particular, NCT03823131 evaluates the efficacy of tavokinogene telseplasmid (tavo) electroporation (EP), pembrolizumab, and epacadostat against unresectable HNSCC (as compared to pembrolizumab monotherapy). Moreover, the tolerability, safety and preliminary efficacy of epacadostat and pembrolizumab were tested in patients affected by (i) advanced pancreatic cancer with chromosomal instability or homologous recombination repair deficiency (HRD) (NCT03432676), (ii) esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma and gastroesophageal adenocarcinoma (NCT03592407), (iii) HNSCC recurring after PD-1/PD-L1 therapy (NCT03463161), and (iv) ovarian clear cell carcinoma (NCT03602586).…”

Trial watch: TLR3 agonists in cancer therapy

“…In particular, Hiltonol™ is being administered in combination with radiotherapy and rhFLT3LG as in situ vaccine supported by systemic pembrolizumab 216 to patients affected by metastatic breast cancer, HNSCC and NHL in the context of a Phase I/II assay (NCT03789097). This combinatorial regimen includes three therapies directed against a “target site”: (1) rhFLT3LG, known also by the name of CDX-301, 217 , 218 that specifically recruits and expands DCs, (2) radiation therapy to the tumor and the draining lymph node (administered at a 10–20 times lower dose compared to the standard for patients with this specific type of neoplasm), 78 and (3) Hiltonol™, which should activate the immune cells recruited into the tumor by rhFLT3LG and radiation.…”