Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Progesterone implants enhance SIV vaginal transmission and early virus load.

Simian immunodeficiency virus (SIV) can cross the intact vaginal epithelium to establish a systemic infection in macaques (mac). Using this SIVmac model, we found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold over that observed in macaques treated with placebo implants and exposed to SIV in the follicular phase of the menstrual cycle. Progesterone treatment also increased the number of SIV DNA-positive cells in the vaginal lamina propria as detected by in situ polymerase chain reaction analysis. Moreover, plasma viral RNA was elevated for the first three months in macaques with progesterone implants, and three of the progesterone-treated macaques developed relatively rapid disease courses. This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.

Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques.

We used the simian immunodeficiency virus (SIV)/rhesus macaque model to study events that underlie sexual transmission of human immunodeficiency virus type 1 (HIV-1). Four female rhesus macaques were inoculated intravaginally with SIVmac251, and then killed 2, 5, 7, and 9 d later. A technique that detected polymerase chain reaction-amplified SIV in situ showed that the first cellular targets for SIV were in the lamina propria of the cervicovaginal mucosa, immediately subjacent to the epithelium. Phenotypic and localization studies demonstrated that many of the infected cells were likely to be dendritic cells. Within 2 d of inoculation, infected cells were identified in the paracortex and subcapsular sinus of the draining internal iliac lymph nodes. Subsequently, systemic dissemination of SIV was rapid, since culturable virus was detectable in the blood by day 5. From these results, we present a model for mucosal transmission of SIV and HIV-1.

Seroreactivity of analogous antigenic epitopes in glycoprotein 120 expressed in HIV-1 subtypes A, B, C, and D.

This article describes the impact of sequence variation on the distribution and seroreactivity of linear antigenic epitopes in gp120 encoded in new Ugandan HIV-1 clones from subtypes A, C, and D, and in North American clones from the B subtype. A region of the env gene encoding the C2 to V5 domains was PCR amplified from the lysates of peripheral blood leukocytes or from short-term cultured isolates. Computer-assisted analyses were conducted on the amino acid sequences to determine the distribution of surface structures in gp120. Despite marked sequence diversity, eight analogous epitopes were predicted for all clades of the virus analyzed. Synthetic peptides comprising the putative principal neutralizing determinant E2[V3], and other B cell epitopes E3[V3-V4], E4[V3-V4], E7[C3], and E8[V5], from a seroprevalent Ugandan isolate, AUG06c, were tested in ELISA for antigenicity with sera from Uganda, New York, and Thailand. Variable magnitudes of seroreactivity were observed for all of the peptides tested. However, a significantly higher degree of serum cross-reactivity was detected with the V3 loop peptide. ELISA reactivities of the same serum panel indicated that V3 loop peptides containing the apical residues GPGR (clones AUG06c and BRT3) or GPGQ (CUG045 and DUG044) were more antigenic and display extensive cross-reactivity as compared to analogous peptides comprising GLGQ (DUG23c), GQGQ (DUG042), or GPWG (BRT1). BETATURN analysis of the divergent V3 loop apical residues showed a good correlation of probable beta-turn occurrence with strong seroreactivity. These findings suggest that the major antigenic specificities in the divergent clades of HIV-1 are well conserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of different donor cells on human immunodeficiency virus type 1 replication and selection in vitro.

We sought to determine the effects of different host cells on human immunodeficiency virus type 1 (HIV-1) infection in vitro. First, 17 primary viruses of various phenotypes were examined for replicative capacity in peripheral blood mononuclear cells (PBMC) from 10 healthy donors. While the range of infection was variable over a 40-fold range, it was substantially less than that previously reported (L. M. Williams and M. W. Cloyd, Virology 184:723-728, 1991). In particular, no donor cells demonstrated total resistance to HIV-1 infection. We next cocultured PBMC from an HIV-1-infected patient with stimulated PBMC from three healthy donors to determine the effect of host cells on selection for a particular HIV-1 quasispecies. By using DNA sequencing, it was found that the dominant quasispecies (AD30-15) after culture was nearly identical in the cells of different donors. Furthermore, after 6 months in vivo, the patient developed a dominant proviral population in PBMC that was most closely related to the quasispecies preferentially selected in vitro, although this quasispecies was only a minor fraction of the sequences present earlier in PBMC. In subsequent biological characterizations, it was found that AD30-15 grew much better in PBMC and macrophages than did other related quasispecies. Hence, we conclude that the primary mechanism of in vitro selection for a particular HIV-1 variant in this case is mediated by the phenotypic properties of the virus and is less dependent on host cell origin. The findings reported here have important practical implications for studies of HIV-1 replication in primary cells derived from healthy donors.

Yeast structural gene (APN1) for the major apurinic endonuclease: homology to Escherichia coli endonuclease IV.

DNA damage generated by oxygen radicals includes base-free apurinic/apyrimidinic (AP) sites and strand breaks that bear deoxyribose fragments. The yeast Saccharomyces cerevisiae repairs such DNA lesions by using a single major enzyme. We have cloned the yeast structural gene (APN1) encoding this AP endonuclease/3'-repair diesterase by immunological screening of a yeast genomic DNA expression library in lambda gt11. Gene disruption experiments confirm that the Apn1 protein accounts for greater than or equal to 97% of both AP endonuclease and DNA 3'-repair diesterase activities in yeast cell-free extracts. The DNA and predicted amino acid sequences for the APN1 gene are homologous to those for the nfo gene encoding DNA endonuclease IV of Escherichia coli. This conservation of structure between a eukaryotic enzyme and its prokaryotic counterpart underscores the fundamental nature of their roles in DNA repair.