In the phase IV, open-label, single-arm study NCT01203917, first-line gefitinib 250 mg/d was effective and well tolerated in Caucasian patients with epidermal growth factor receptor (EGFR) ...mutation-positive non–small-cell lung cancer (previously published). Here, we report EGFR mutation analyses of plasma-derived, circulating-free tumor DNA.
Mandatory tumor and duplicate plasma (1 and 2) baseline samples were collected (all screened patients; n = 1060). Preplanned, exploratory analyses included EGFR mutation (and subtype) status of tumor versus plasma and between plasma samples. Post hoc, exploratory analyses included efficacy by tumor and plasma EGFR mutation (and subtype) status.
Available baseline tumor samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Mutation status concordance between 652 matched tumor and plasma 1 samples was 94.3% (95% confidence interval CI, 92.3–96.0) (comparable for mutation subtypes); test sensitivity was 65.7% (95% CI, 55.8–74.7); and test specificity was 99.8% (95% CI, 99.0–100.0). Twelve patients of unknown tumor mutation status were subsequently identified as plasma mutation-positive. Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known). Mutation status concordance between 224 matched duplicate plasma 1 and 2 samples was 96.9% (95% CI, 93.7–98.7). Objective response rates are as follows: mutation-positive tumor, 70% (95% CI, 60.5–77.7); mutation-positive tumor and plasma 1, 76.9% (95% CI, 65.4–85.5); and mutation-positive tumor and mutation-negative plasma 1, 59.5% (95% CI, 43.5–73.7). Median progression-free survival (months) was 9.7 (95% CI, 8.5–11.0; 61 events) for mutation-positive tumor and 10.2 (95% CI, 8.5–12.5; 36 events) for mutation-positive tumor and plasma 1.
The high concordance, specificity, and sensitivity demonstrate that EGFR mutation status can be accurately assessed using circulating-free tumor DNA. Although encouraging and suggesting that plasma is a suitable substitute for mutation analysis, tumor tissue should remain the preferred sample type when available.
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed ...the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer.
Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments.
There was no significant difference in PFS between treatment arms (hazard ratio HR, 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed.
This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.
Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature ...was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Eligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC(60 )and K(trans)) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57.
Twenty-two patients received vandetanib (n = 10, 100 mg; n = 12, 300 mg). Baseline measurements of iAUC(60 )and K(trans )were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC(60), and -4.6% (100 mg) and -2.7% (300 mg) for K(trans); these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg (P = 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease >/=8 weeks.
In this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC(60 )and K(trans).
NCT00496509 (ClinicalTrials.gov); D4200C00050 (AstraZeneca).
A phase II study (ClinicalTrials.gov identifier: NCT00628251) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or ...partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.
In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population.
Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2%
51.4%; odds ratio OR, 2.53 95% CI, 1.40 to 4.58;
= .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 95% CI, 1.42 to 8.54). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 95% CI, 0.43 to 0.91;
= .013; median, 13.4
9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy.
Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.
Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA ...mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD.
•Several biomarker tests are available to determine patient selection for PARPis.•These tests identify tumours with HRD and help determine sensitivity to PARPis.•We reviewed biomarker tests to assess HRD and their relevance for PARPi treatment.
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Background: Although regularly used in breast and gastric cancer, HER2 testing is not routinely performed in colorectal cancer (CRC). Immunohistochemistry (IHC) and in situ hybridization (ISH) ...scoring have not been optimized for assessment of HER2 overexpression and amplification in CRC. Varying rates of HER2 overexpression (2%-11%) have been reported in previously untreated CRC (Wang World J Gastrointest Oncol 2019) and patients with advanced/metastatic CRC with HER2 amplification or overexpression respond poorly to current standard of care therapies (Sartore-Bianchi Oncologist 2019). We characterized HER2 prevalence in a retrospective cohort analysis of clinical trial patients. Methods: The HORIZON III trial (NCT00384176) evaluated FOLFOX + bevacizumab or cediranib (AZD2171) as first-line (1L) treatment in patients with metastatic CRC (Schmoll J Clin Oncol 2012). The primary objective of this analysis of a subset of HORIZON III samples was to characterize HER2 prevalence in 1L metastatic CRC. Secondary and exploratory objectives included correlating HER2 status to other molecular findings (eg, RAS/RAF mutations), clinicopathologic characteristics, and patient outcomes. IHC was performed using a monoclonal anti-HER2 antibody PATHWAY HER2 4B5 Ventana on primary CRC tumor sections and scored according to ASCO/CAP guidelines for gastric cancer (Bartley Arch Pathol Lab Med 2016). H&E staining was performed to determine the adequacy of tumor samples (ie, > 100 viable tumor cells per specimen). All tumors with an IHC score of 2+ were analyzed for amplification by ISH (HER2 IQFISH pharmDx dual probe kit, Agilent Technologies K573111-5). Targeted mutation panel testing was used to determine other molecular alterations. Descriptive statistics were used to summarize baseline and clinical outcome data by HER2 status. The current analysis was approved by the AstraZeneca bioethics review board. Results: Of the 1614 patients in HORIZON III, 396 met the inclusion criteria of appropriate consent, sufficient tumor sample for analysis, and a unique identifier. HER2-positive tumors (IHC3+ or IHC2+/ISH+) were identified in 2.1% of samples; 1.3% were IHC3+ and 0.8% were IHC2+/ISH+. Compared with IHC3+, IHC2+ tumors were more heterogeneous with mixed components of cells weakly expressing HER2 and lacking HER2 expression. Conclusions: This exploratory analysis of the HORIZON III study provides insights into HER2 prevalence in 1L, unselected, advanced/metastatic CRC, finding that 2.1% of tumors were HER2 positive. The demographic characteristics of patients with analyzable samples were representative of the entire HORIZON III study population; however, further assessment of KRAS status and other clinicopathological characteristics is needed. These data may inform future clinical development and support selection of patients with CRC who are likely to benefit from HER2 targeting therapies. Clinical trial information: NCT00384176 .
5559
Background: PARP inhibitors exploit synthetic lethality in tumor cells with deficiency in homologous recombination repair (HRR). In line with this, most reported mechanisms of PARP inhibitor ...resistance restore HRR. Of multiple resistance mechanisms reported preclinically, reversion mutations in BRCA genes are the only confirmed mechanism of resistance to both platinum and PARP inhibitors in patients (pts) to date (Lin K et al. Cancer Discov 2019), with most studies focusing on ovarian cancer. MMEJ is an alternative DNA damage repair pathway, in which DNA polymerase θ (POLθ) has a key role; MMEJ has been suggested to play a role in BRCA reversion mutations (Tobalina L et al. Ann Oncol 2021). Methods: Targeted circulating tumor DNA (ctDNA) sequencing analyzed over 500 plasma samples collected at baseline and at progression to therapy in pts with ovarian or breast cancer and a mutation in BRCA1 and/or BRCA2 (BRCAm) who were treated with olaparib or chemotherapy in one of three Phase II/III clinical studies (LIGHT NCT02983799, SOLO3 NCT02282020, OlympiAD NCT02000622). Only pts with an original pathogenic BRCAm detected in ctDNA were evaluable. BRCA reversion mutations were identified using internal computational framework; DNA sequences surrounding BRCA reversion sites were analyzed for MMEJ signatures. Results: At baseline, in pooled data across treatment arms and across all available samples, BRCA reversion mutations were detected in 4/114 (3.5%) and 6/133 (4.5%) of breast and ovarian cancer pts, respectively, which may have developed on prior platinum therapy. At progression, BRCA reversion mutations were detected in 34/79 (43%) breast cancer pts and in 26/101 (26%) ovarian cancer pts who received olaparib, with at least 2/79 and 4/101 reversions already present at baseline, respectively. At progression, in the chemotherapy arm, BRCA reversion mutations were detected in 3/34 (9%) breast cancer pts and 1/29 (3%) ovarian cancer pts, with 2/34 and 0/29 reversions present at baseline, respectively. Reversion mutations varied in allelic frequency and were either present as single or multiple reversions, suggesting multiple events within the tumor were driving resistance. The location and type of reversion mutations reflected the functional importance of BRCA protein domains. A large proportion of BRCA reversion mutations (47/69 68% that were evaluable) were mediated by the MMEJ pathway based on the presence of MMEJ signatures around BRCA reversion sites. Conclusions: We detected BRCA reversion mutations in at least ̃40% of breast and ̃20% of ovarian cancer pts following treatment with olaparib. A large proportion of these reversion mutations are likely to have been mediated by MMEJ repair, suggesting that POLθ inhibitors in combination with platinum or PARP inhibitors might prevent or delay emergence of PARP inhibitor resistance. Clinical trial information: NCT02983799, NCT02282020, NCT02000622.
The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer.
PARP ...inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined.
Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% 4/15; 95% confidence interval (CI), 7.8-55.1, while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group.
Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.
Background: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly ...diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. Methods: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. Results: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64–0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64–0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. Conclusion: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.
Olaparib is a poly ADP‐ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure‐response analyses were performed to ...evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposure‐progression‐free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure‐safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.
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