First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from part B of the JAVELIN Merkel 200 study.

BACKGROUND: Results from the JAVELIN Merkel 200 study led to the approval of avelumab [an anti-programmed death-ligand 1 (PD-L1) antibody] for the treatment of metastatic Merkel cell carcinoma (mMCC) in multiple countries and its inclusion in the treatment guidelines as a preferred or recommended therapy in this setting. Here, we report 4-year follow-up results from the cohort of patients with mMCC who received avelumab as first-line treatment. PATIENTS AND METHODS: In part B of JAVELIN Merkel 200, a single-arm, open-label, phase II study, patients with mMCC who had not received prior systemic therapy for metastatic disease received avelumab 10 mg/kg via intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term overall survival (OS), patient disposition, and subsequent treatment were analyzed. RESULTS: In total, 116 patients received first-line avelumab. At the data cutoff (2 February 2022), the median follow-up was 54.3 months (range 48.0-69.7 months). Seven patients (6.0%) remained on treatment and an additional 21 patients remained in follow-up (18.1%); 72 patients (62.1%) had died. The median OS was 20.3 months [95% confidence interval (CI) 12.4-42.0 months], with a 4-year OS rate of 38% (95% CI 29% to 47%). In patients with PD-L1+ or PD-L1- tumors, the 4-year OS rate was 48% (95% CI 26% to 67%) and 35% (95% CI 25% to 45%), respectively. In total, 48 patients (41.4%) received poststudy anticancer drug therapy, most commonly etoposide (20.7%), carboplatin (19.0%), and avelumab (12.1%). CONCLUSIONS: Avelumab first-line monotherapy in patients with mMCC resulted in meaningful long-term OS, which compared favorably with historical studies of first-line chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

Plasma HPV cell-free DNA monitoring in advanced HPV-associated oropharyngeal cancer.

Background: Measuring cell-free (cf)DNA in blood and tissues holds significant potential as a minimally invasive method for disease monitoring in cancer. Cancers arising in the oropharynx and causally linked to human papillomavirus (HPV) represent an ideal model in which to interrogate these methods. Patients and methods: We designed an ultrasensitive and quantitative droplet digital (dd)PCR assay to detect the five dominant high-risk HPV subtypes linked to oropharyngeal cancer (OPC). We enrolled a pilot observational cohort of 22 patients with advanced HPV+ OPC to evaluate the clinical utility of our assay and explore its predictive and prognostic potential. Results: Total tumor burden (TTB) strongly correlated with HPV cfDNA levels (R = 0.91, P = 2.3×10-6) at this cohort size, and in most cases more distant anatomic disease locations predicted increasing HPV cfDNA levels. All participants demonstrated a corresponding change in their HPV cfDNA levels at a median of 16 days (range 12-38) before restaging scans confirming treatment response or progression. Patients with locoregional disease in the head and neck or pulmonary-only metastases had worse outcomes (P = 0.01). Both TTB and median plasma HPV cfDNA levels negatively correlated with survival (R=-0.65, P = 0.01; R=-0.48, P = 0.05, respectively). Conclusion(s): Plasma HPV cfDNA monitoring recapitulates fluctuations in disease status. While blood-based HPV DNA monitoring does not currently have a role in managing HPV+ OPC, these data speak to their broad clinical potential in an era of precision medicine.

Tumor PD-L1 expression is associated with improved survival and lower recurrence risk in young women with oral cavity squamous cell carcinoma.

Young patients with oral cavity squamous cell carcinoma (OCSCC) are often recognized as a distinct epidemiological cohort. In this study, genomic and immune-based metrics were correlated with long-term outcomes for a young patient population treated at a single institution. A fully clinically annotated, retrospective cohort of 81 patients aged ≤45 years with OCSCC is described, and the impact of clinicopathological features on long-term survival outcomes is reported. Genomic and immune parameters were integrated utilizing a whole-exome sequencing and immunohistochemical approach among females in the cohort. It was found that young OCSCC patients had favorable outcomes (10-year disease-free survival 79.1%, overall survival 80.0%) regardless of sex, particularly if they presented with oral tongue primaries and early stage disease. While mutational analysis appeared similar to that of older patients with OCSCC who lack a smoking history, a comparatively high degree of PD-L1 expression and PD-1/L1 concordance (P=0.001) was found among young female OCSCC patients. Subjects with greater membranous PD-L1 positivity and the presence of tumor-infiltrating lymphocytes had a decreased risk of recurrence (P=0.01 and P=0.01, respectively) and improved survival (P=0.04 and P=0.03, respectively). These findings warrant further validation and support the investigation of immunotherapeutic approaches targeting PD-1/L1 interactions in young OCSCC patients.

Randomized, placebo-controlled single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics of the HIV nucleoside reverse transcriptase inhibitor, BMS-986001, in healthy subjects.

The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS-986001 as a single oral dose in healthy male subjects. Sixty-four healthy male subjects were randomized to receive a single dose of BMS-986001 or placebo in this single-blind, placebo-controlled, sequential ascending-dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS-986001 n = 6/placebo n = 2). BMS-986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS-986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS-986001 was rapidly absorbed and exhibited a linear dose-exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS-986001 as a single dose was generally safe and well tolerated. A linear dose-exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.

Measuring the volume of a fluid in a diamond anvil cell using a confocal microscope.

Confocal microscopy is a potentially powerful technique for obtaining equation-of-state (EOS) data for fluids in a diamond anvil cell. Unlike conventional microscopy, a confocal microscope scans the cell in three dimensions. From the intensity profile of the reflected laser light, we calculated the index of refraction and optical thickness of the sample contained in the cell. These measurements, combined with the cross-sectional area of the sample, enabled us to calculate the volume. As a test of the experimental technique and analysis, we produced a pressure-volume curve for liquid water at 300 K. The results agree with published EOS data within experimental error.

Formation of atomic tritium clusters and bose-einstein condensates.

We present an extensive study of the static and dynamic properties of systems of spin-polarized tritium atoms. In particular, we calculate the two-body |F,m(F)>=|0,0> s-wave scattering length and show that it can be manipulated via a Feshbach resonance at a field strength of about 870 G. Such a resonance might be exploited to make and control a Bose-Einstein condensate of tritium in the |0,0> state. It is further shown that the quartet tritium trimer is the only bound hydrogen isotope and that its single vibrational bound state is a Borromean state. The ground state properties of larger spin-polarized tritium clusters are also presented and compared with those of helium clusters.

Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo.

The human immunodeficiency virus type 1 protease mutation N88S, which is occasionally selected by treatment with nelfinavir or indinavir, confers hypersusceptibility to amprenavir in vitro. The clinical relevance of this observation is unclear. We report a case of N88S developing after virologic failure of both indinavir- and nelfinavir-containing regimens that was managed successfully with a regimen that contained amprenavir.

Clinical use of genotypic and phenotypic drug resistance testing to monitor antiretroviral chemotherapy.

Assays that detect antiretroviral drug resistance in human immunodeficiency virus have recently become available to clinicians. Phenotypic assays measure the drug susceptibility of the virus by determining the concentration of drug that inhibits viral replication in tissue culture. Genotypic assays determine the presence of mutations that are known to confer decreased drug susceptibility. Although each type of assay has specific advantages, limitations associated with these tests often complicate the interpretation of results. Several retrospective clinical trials have suggested that resistance testing may be useful in the assessment of the success of salvage antiretroviral therapy. Prospective, controlled trials have demonstrated that resistance testing improves short-term virological response. Resistance testing is currently recommended to help guide the choice of new drugs for patients after treatment has failed and for pregnant women. Resistance testing should also be considered for treatment-naïve patients, to detect transmission of resistant virus.

Testing for HIV-1 drug resistance.

Viral resistance to antiretroviral agents may limit the efficacy of current treatment regimens for HIV-1 infection. The mutational patterns underlying resistance to each antiretroviral agent are often quite diverse, and cross-resistance patterns in each of the currently available classes are complex. Current methods for determining drug resistance include genotypic and phenotypic assays, and each has advantages and limitations. Prospective clinical trials assessing the utility of HIV-1 drug resistance testing have shown significant but modest improvement in virologic outcomes with genotypic assays. Some, but not all, trials of phenotypic resistance testing have demonstrated improved virologic outcomes. Resistance testing is currently recommended for patients who have virologic failure or have no response to an antiretroviral regimen, and for pregnant women. Testing should also be considered in treatment-naive patients in areas of high prevalence of transmitted drug-resistant virus.

Comparative analysis of HIV type 1 genotypic resistance across antiretroviral trial treatment regimens.

From data on HIV-1 genotypes collected from antiretroviral trial participants who fail virologically, we describe methods for comparing distributions of acquired HIV-1 mutations across different treatment regimens. Given a definition of a "mutational distance" that summarizes the genetic change of a subject's virus in a way that captures the resistance cost of exposure to an antiretroviral regimen, these comparative analyses inform about the relative treatability of emergent virus by next-line therapy directed to the same viral target. The utility of the methods is illustrated by application to data from AIDS Clinical Trials Group (ACTG) Study 241. We find that patients failing zidovudine/didanosine/nevirapine accumulated a 2.41-fold greater nonnucleoside reverse transcriptase inhibitor (RTI) mutational distance than patients failing zidovudine/didanosine [95% confidence interval (1.55, 5.26), p < 0.000001], quantitating expectations that adding a nonnucleoside RTI to a double nucleoside regimen may attenuate future effectiveness of nonnucleoside RTI therapy for nucleoside-experienced patients if viremia is not suppressed. We also find that persons with extensive prior experience with suboptimal nucleoside therapy who were virologically failing zidovudine/didanosine/nevirapine or zidovudine/didanosine accumulated a similar nucleoside RTI mutational distance, implying that the addition of the nonnucleoside RTI did not preserve future nucleoside options.

Antiretroviral resistance during successful therapy of HIV type 1 infection.

HIV type 1 (HIV-1) drug resistance mutations were selected during antiretroviral therapy successfully suppressing plasma HIV-1 RNA to <50 copies/ml. New resistant mutant subpopulations were identified by clonal sequencing analyses of viruses cultured from blood cells. Drug susceptibility tests showed that biological clones of virus with the mutations acquired during successful therapy had increased resistance. Each of the five subjects with new resistant mutants had evidence of some residual virus replication during highly active antiretroviral therapy (HAART), based on transient episodes of plasma HIV-1 RNA > 50 copies/ml and virus env gene sequence changes. Each had received a suboptimal regimen before starting HAART. Antiretroviral-resistant HIV-1 can be selected from residual virus replication during HAART in the absence of sustained rebound of plasma HIV-1 RNA.

Comparison of sequencing by hybridization and cycle sequencing for genotyping of human immunodeficiency virus type 1 reverse transcriptase.

The performances of two methods of nucleotide sequencing were compared for the detection of drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase (RT) in viruses isolated from highly RT inhibitor-experienced individuals. Of 11,677 amino acids deduced from population PCR products by both cycle sequencing and sequencing by hybridization to high-density arrays of oligonucleotide probes, 97.4% were concordant by both methods, 0.8% were discordant, and 1.7% had an ambiguous determination by at least one method. A higher rate of discordance (3.9%) was observed among RT inhibitor resistance-associated codons. In 45% of the isolates, RT codon 67 was deduced as the wild-type Asp by hybridization sequencing but as the zidovudine resistance-associated Asn by cycle sequencing. In other resistance-associated codon discordances, cycle sequencing also more commonly called a known resistance-associated amino acid than hybridization sequencing did. The nucleotide sequence in the vicinity of several codons with discordant calls influenced population-based hybridization sequencing. For isolates evaluated by additional sequencing of molecular clones of PCR products by both methods, the discordance between methods was less frequent (0.4% of all 5,994 amino acids and 0 of 494 drug resistance-associated codons). At positions which were discordant or ambiguous in the population sequences, the results of sequencing of clones by both methods were usually in agreement with the population cycle sequencing result. In summary, most RT codons were highly concordant by both methods of population-based sequencing, with discordances due in large part to genetic mixtures within or adjacent to discordant codons.

Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine.

Resistance mutations selected in reverse transcriptase (RT) by incompletely suppressive therapy with combination zidovudine and didanosine with or without nevirapine were identified in 141 human immunodeficiency virus type 1 isolates from peripheral blood mononuclear cells of 57 individuals in the AIDS Clinical Trials Group protocol 241. After prolonged treatment (16-48 weeks), the most common nevirapine-selected mutations were RT 181C (15/30 isolates [50%]), 190A (15/30 [50%]), and 101E (9/30 [30%]). RT 103N and 188L, which individually confer cross-resistance to all nonnucleoside RT inhibitors, were seen in a minority of viruses (6/30 [20%] and 4/30 [13%], respectively). Didanosine-resistance mutations arose rarely. A newly recognized mutation, RT 44D, was selected by the nucleosides. Two distinct zidovudine-resistance mutational patterns were noted. Mutations selected during treatment with zidovudine, didanosine, and nevirapine differed among individuals and changed over time. Resistance testing is necessary to identify which mutations are selected by nevirapine-containing combinations.