Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. ...Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in
colorectal cancer models. Patients with ...refractory
-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (
= 28) or without (
= 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with
-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.
Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with
-mutant mCRC.
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•The human microbiome consisting of microorganisms living on and in the human body, their collective genomes and metabolic products has been implicated in many disease processes including cancer.•An ...emerging body of literature suggests an important role for the gut microbiome in modulating response to immune checkpoint blockade across different cancer types.•Microbiome composition should be measured, analyzed and reported using standard techniques and methodology.•There are multiple interventional strategies that can be used to modify the microbiome, including diet, prebiotics, probiotics, fecal microbiota transplantation, microbial consortia and stool substitutes, and antibiotics to sterilize selected taxa.•Proof-of-principle and proof-of-concept clinical trials with appropriate controls are needed to demonstrate safety, efficacy and clinical utility of human microbiome modulation in cancer.
The human microbiome comprising microorganisms, their collective genomes and metabolic products has gained tremendous research interest in oncology, as multiple cohorts and case studies have demonstrated discernible interpatient differences in this ecosystem based on clinical variables including disease type, stage, diet, antibiotic usage, cancer treatments, therapeutic responses and toxicities. The modulation of the gut microbiome is the subject of many ongoing preclinical and clinical investigations, through the manipulation of diet, as well as the use of prebiotics, probiotics, specific antibiotics, fecal microbial transplantation, microbial consortia and stool substitutes. Standardization and quality control are needed to maximize the information being generated in this growing field, ranging from technical assays to measure microbiome composition, to methodological aspects in the analysis and reporting of results. Proof-of-mechanism and proof-of-concept clinical trials with appropriate controls are needed to confirm or refute the feasibility, safety and ultimately the clinical utility of human microbiome modulation in cancer patients.
Clinical trials represent a fulcrum for oncology drug discovery and development to bring safe and effective medicines to patients in a timely manner. Clinical trials have shifted from traditional ...studies evaluating cytotoxic chemotherapy in largely histology-based populations to become adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in selected patient subsets. This review will discuss the scientific, methodological, practical, and patient-focused considerations to transform clinical trials. A call to action is proposed to establish the framework for next-generation clinical trials that strikes an optimal balance of operational efficiency, scientific impact, and value to patients. SIGNIFICANCE: The future of cancer clinical trials requires a framework that can efficiently transform scientific discoveries to clinical utility through applications of innovative technologies and dynamic design methodologies. Next-generation clinical trials will offer individualized strategies which ultimately contribute to globalized knowledge and collective learning, through the joint efforts of all key stakeholders including investigators and patients.
Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 ...(IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9–10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.)
Background
The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT‐hypo) ...during the COVID‐19 pandemic.
Methods
HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT‐hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT‐acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005‐2017 were included. Locoregional control (LRC) and distant control (DC) after RT‐hypo, RT‐acc, and CCRT were compared for various subgroups.
Results
The study identified 994 human papillomavirus–positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT‐hypo, RT‐acc, and CCRT, respectively) and 1045 HPV– HNSCC cases (with 263, 451, and 331 receiving RT‐hypo, RT‐acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy‐alone patients were older. The median follow‐up was 4.6 years. RT‐hypo, RT‐acc, and CCRT produced comparable 3‐year LRC and DC for HPV+ T1‐2N0‐N2a disease (seventh edition of the TNM system TNM‐7; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1‐T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1‐2N2c/T3N0‐N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT‐hypo or RT‐acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV– HNSCC, 3‐year LRC and DC were similar with RT‐hypo, RT‐acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT‐hypo and RT‐acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT‐acc (62%) but not RT‐hypo (80%) or CCRT (92%; RT‐hypo vs CCRT: P = .270; RT‐acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT‐hypo or RT‐acc in stage IV (73%, 65%, and 66%; P = .336).
Conclusions
It is proposed that RT‐hypo be considered in place of CCRT for HPV+ T1‐T3N0‐N2c (TNM‐7) HNSCCs, HPV– T1‐T2N0 HNSCCs, and select stage III HNSCCs during the COVID‐19 outbreak.
Hypo‐fractionated radiotherapy has disease control comparable to that of chemoradiotherapy in select head and neck cancers, and it is a potential alternative for this subgroup during the COVID‐19 pandemic.
Immune checkpoint blockade (ICB) has become a standard of care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from ...treatment. Quantification of plasma circulating tumour DNA (ctDNA) levels and on-treatment kinetics may permit real-time assessment of disease burden under selective pressures of treatment.
R/M HNSCC patients treated with systemic therapy, platinum-based chemotherapy (CT) or ICB, underwent serial liquid biopsy sampling. Biomarkers tested included ctDNA measured by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) and markers of host inflammation measured by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).
Among 53 eligible patients, 16 (30%) received CT, 30 (57%) ICB anti-PD1/L1 monotherapy and 7 (13%) combination immunotherapy (IO). Median progression-free survival (PFS) and overall survival (OS) were 2.8 months (95% CI, 1.3–4.3) and 8.2 months (95% CI, 5.6–10.8), respectively. Seven (13%) patients experienced a partial response and 21 (40%) derived clinical benefit. At baseline, median ctDNA variant allele frequency (VAF) was 4.3%. Baseline ctDNA abundance was not associated with OS (p = 0.56) nor PFS (p = 0.54). However, a change in ctDNA VAF after one cycle of treatment (ΔVAF (T1–2)) was predictive of both PFS (p< 0.01) and OS (p< 0.01). Additionally, decrease in ΔVAF identified patients with longer OS despite early radiological progression, 8.2 vs 4.6 months, hazard ratio 0.44 (95% CI, 0.19–0.87) p = 0.03. After incorporating NLR and PLR into multivariable Cox models, ctDNA ∆VAF retained an association with OS.
Early dynamic changes in ctDNA abundance, after one cycle of treatment, compared to baseline predicted both OS and PFS in R/M HNSCC patients on systemic therapy.
•Baseline ctDNA was not associated with progression free or overall survival (OS).•A change in ctDNA after one cycle of treatment was predictive of survival.•A decrease in ctDNA (T1-2) corresponded with longer OS despite radiological progression.•Low NLR was associated with improved OS.
We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations.
This first-in-human phase 1 ...study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily QD) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety.
A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively.
Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.
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