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  • 1
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    Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: A phase Ib/II study.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 3_suppl ( 2021-01-20), p. 312-312
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. 312-312
    Abstract: 312 Background: Silmitasertib (CX-4945), an oral small molecule inhibitor of casein kinase 2 (CK2), has exhibited preclinical antitumor activity and strong synergism with gemcitabine + cisplatin. We investigated the safety and efficacy of silmitasertib in combination with gemcitabine + cisplatin in patients with unresectable cholangiocarcinoma (CCA). Methods: S4-13-001 is a multicenter, open-label, phase Ib/II study of silmitasertib in combination with gemcitabine + cisplatin in patients with locally advanced or metastatic CCA. The phase Ib portion included dose-escalation, expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg bid (6 days for the escalation/expansion cohorts and 10 and 21 days’ continuous dosing for the exploratory cohorts). In the phase II portion patients received silmitasertib 1000 mg bid for 10 days in combination with gemcitabine + cisplatin on days 1 & 8 over a 21-day cycle. In this interim analysis, we present findings from the combined population of patients from the phase Ib and II portions of the study. Response to treatment was assessed by RECIST v1.1 every 6 weeks. Primary efficacy outcome measure was progression-free survival (PFS). ClinicalTrials.gov (NCT02128282). Results: A total of 87 patients were enrolled and received silmitasertib in the phase Ib (n=50) and phase II (n=37) portions of the study. Of these, 55 patients were evaluable for efficacy with details as follows: median PFS 11.1 (95% CI 7.6–14.7) months; median overall survival (OS) 17.4 (95% CI 13.4–25.7) months; overall response rate (ORR) 32.1%; and disease control rate (DCR) 79.3%. Almost all patients (79/87; 90.8%) evaluable for safety reported ≥1 treatment-related adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib were diarrhea (65.5%), nausea (50.6%), vomiting (33.3%), fatigue (31.0%), and anemia (21.8%). The most common grade ≥3 TEAEs were diarrhea (13.8%), neutropenia (11.5%), nausea (9.2%), anemia (8.0%), and thrombocytopenia (8.0%). Eleven patients (12.6%) discontinued treatment due to TEAEs. Conclusions: Silmitasertib in combination with gemcitabine + cisplatin yields promising preliminary evidence of efficacy in patients with locally advanced or metastatic CCA. Based on these data a randomized phase III trial is planned. Clinical trial information: NCT02128282.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.3_suppl.312
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 2
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    CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in patients with advanced neuroendocrine tumors (NETs)—A phase IIa study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e16235-e16235
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16235-e16235
    Abstract: e16235 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. The Phase I trial in Asia determined an MTD of 600 mg daily (300 mg BID) with a favorable safety profile. The best response was stable disease with measurable tumor reduction in one patient with NET. We present preliminary results for this ongoing Phase IIa study. Methods: Eligible patients had advanced NETs (low/intermediate grade lung or WHO grade 1 or 2 gastrointestinal or pancreatic origin) which were refractory to standard of care therapy and progressed within 6 months prior to screening. Patients received oral CVM-1118 at 200 to 300 mg BID (400 to 600 mg daily) in 28-day cycles. Pharmacokinetics (PK) was assessed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of overall response (DoR), time-to-progression (TTP), and overall survival (OS). Planned enrollment is 33 evaluable patients. Results: As of February 10, 2023, 30 patients were enrolled, of which 21 evaluable patients (12 M/9 F; median age 61 y, range 37–82 y) were predominately grade 2 pNET (12/21, 57%) or GI NET (8/21, 38%). The majority (14/21, 67%) had disease progression after prior treatment with chemotherapy or small molecule inhibitor (median of 1 prior therapy). The duration of CVM-1118 treatment ranged from 1.4–34.6 mos (median 3.8 mos) with 4/21 (19%) patients remaining on treatment for more than 20 mos (range 22–34 mos). The median PFS was 6.9 mos (95% CI 3.3–10.3 mos), which exceeded the historical estimate for PFS of 4–6 mos (Raymond et al., 2011; Yao et al., 2016). The 8-mo and 12-mo PFS rates were 42% (95% CI 25–64%) and 29% (95% CI 14–50%), respectively. The DCR was 66.7% (95% CI 45–83%) with an ORR of 4.8% (1 PR with ongoing tumor reduction of 46% in pNET group). The most common treatment-related AEs ≥ grade 3 included ALT/AST increased (3.3%), diarrhea (3.3%), anemia (3.3%), neutrophil count decreased (3.3%), and tumor lysis syndrome (3.3%). No CVM-1118-related SAEs were reported. PK results showed CVM-1118 was rapidly metabolized to the active metabolite CVM-1125 in all patients following oral dosing. On Day 1, the mean drug exposure of CVM-1125 was C max 418 ng/mL and AUC 0-24 2170 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T 1/2 of CVM-1125 was ~2.2 hr. No clear correlation between drug exposure and adverse effects or tumor reduction was observed. Conclusions: CVM-1118 has demonstrated a durable DCR with acceptable safety and tolerability. PK results showed good drug exposure with T 1/2 of CVM-1125 ~2.2 hr. These data support future studies in patients with advanced NETs. Raymond E et al., 2011. N Eng J Med 364(6): 501-513. Yao JC et al., 2016. Lancet 387(10022): 968-977. Clinical trial information: NCT03600233 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e16235
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
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    A phase II study of ADI-PEG 20 and FOLFOX6 in patients (pts) with advanced hepatocellular carcinoma (HCC).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 4_suppl ( 2019-02-01), p. TPS477-TPS477
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 4_suppl ( 2019-02-01), p. TPS477-TPS477
    Abstract: TPS477 Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in HCC models. A prior phase 1 study of FOLFOX6 and ADI-PEG 20 established the safety and recommended phase 2 dose of the combination in pts with advanced gastrointestinal tumors (Harding et al. CCP 2018). For 23 treatment-refractory HCC pts who were treated at the recommended phase 2 dose on an expansion cohort of the phase 1, the objective response rate (ORR) was 21% (95% CI 7.5-43.7) and median progression-free survival (PFS) was 7.3 months. These data were favorable when compared to historic data for FOLFOX alone where the ORR was ~8% and PFS was 2.93 months and suggest greater clinical activity of the combination (Qin et al. JCO 2013). Prospective confirmation of these results is required. Methods: This is an international, multicenter, single-arm, open-label phase 2 trial of ADI-PEG 20 and FOLFOX6 for advanced HCC pts with Child-Pugh A liver function who progressed on ≥ 2 prior lines of prior systemic therapy (NCT02102022). The primary objective is to define the ORR by RECIST 1.1 as assessed by blinded independent central review. Secondary objectives include determination of safety, disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), serum arginine, citrulline and anti-ADI-PEG 20 levels over 24 weeks, and alpha-fetoprotein response. Eligible pts receive intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 36 mg/m. 2 Cross-sectional imaging will be completed every 8 weeks until progression of disease. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. Clinical trial information: NCT02102022.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.4_suppl.TPS477
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Online Resource
    Trastuzumab emtansine (T-DM1) in advanced cancers with HER2 mutations or amplification: Results from the Molecular Screening and Therapeutics (MoST) Program substudy.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3127-3127
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3127-3127
    Abstract: 3127 Background: The antibody-drug conjugate T-DM1 is widely used for the treatment of HER2-positive metastatic breast cancer. Its activity in other advanced solid tumors harboring HER2 alterations identified by comprehensive genomic profiling (CGP) needs further characterization. Methods: The MoST program provides a precision oncology framework for screening patients (pts) by CGP to identify genomic alterations with potential to match to biomarker-directed clinical trials. This multi-center, single-arm phase 2 trial (ACTRN12619001265167) enrolled adult pts with refractory solid tumors (excluding breast and gastroesophageal cancers) with HER2 alterations. This trial recruited 2 groups of 16 pts (group 1: mutations, group 2: genomic amplification, defined as copy number ≥ 6 copies). The primary composite endpoint was objective tumor response (OTR) assessed by RECIST 1.1 and time-to-progression (TTP) ratio (defined as TTP on T-DM1: TTP1 on prior line of systemic therapy). Anti-tumor activity of T-DM1 was confirmed if ≥3 of each 16 pt group achieved an OTR. Key secondary endpoints were progression-free and overall survival (PFS and OS) and safety as assessed by CTCAE 5.0. Results: 32 pts had a median age of 64 years (interquartile range [IQR] 53 to 69); 94% an ECOG PS ≤1; 53% female; and median 2 (IQR 1 to 3.5) prior lines of systemic therapy. The cohort included non-small cell lung cancer (NSCLC, n=12), colorectal (CRC, n=5), salivary gland (SGC, n=5), ovarian (n=3), uterine (n=2), gallbladder (n=2), and 1 each of bladder, pancreas and cervix cancers. After a median follow-up of 17 months (mo), the primary endpoint was met with 7 pts (22%) achieving an OTR, including 3 pts (19%) in group 1 (2 NSCLC and 1 SGC) and 4 pts (25%) in group 2 (3 SGC, and 1 uterine serous carcinoma [USC] ). Fourteen of 29 TTP-evaluable pts (48%) achieved a TTP ratio ≥1.3, including 10 pts without an OTR: equating to 53% (n=17) deriving clinical benefit. The median PFS and OS were 4.5 (95% CI 2.1 to 7.0) and 18.23 mo (95% CI 8.11 to not reached) respectively and 6 mo PFS rate 44% (95% CI 26 to 60%). The (NSCLC) responders in group 1 harbored exon 20 insertions (Y772_A775dup and G778_P780dup ) and the SGC, a L755S mutation. None of the S310Y/F mutations (n=5, including 2 NSCLCs) had an OTR. The USC was ERBB2 amplified (18 copies) on CGP, discordant with in situ hybridisation (ISH) testing results. Overall, 4 pts had CGP-amplified, ISH negative tumors, of whom 2 achieved an OTR. No responses were seen in CRC pts (all RAS/ BRAF-wildtype and IHC 2-3+). No new safety concerns for T-DM1 were reported. Conclusions: T-DM1 has anti-tumor activity across a heavily treated, diverse range of cancer types with HER2 alterations identified by CGP, including several unidentified by standard ISH testing. We await results from our partner trial in the first line advanced NSCLC setting to corroborate the group 1 findings. Clinical trial information: ACTRN12619001265167 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3127
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Genomic therapy matching in rare and refractory cancers: Updated results from a retrospective cohort study in the Molecular Screening and Therapeutic (MoST) program.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 1540-1540
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 1540-1540
    Abstract: 1540 Background: Biomarker actionability and therapy matching are two central concepts in precision oncology. However, the best strategy to align therapy with genomic alterations remains unclear. Here we report the updated results from a cohort study conducted in an Australian precision oncology program (MoST, ACTRN12616000908437), examining a therapy matching strategy based on comprehensive genomic profiling (CGP) results. Methods: All patients (pts) with rare or advanced solid tumours undergoing CGP from 2016 to 2021 after exhausting standard treatments were included. The primary outcome was overall survival (OS) from the date of CGP result, estimated using the Kaplan-Meier method. Pts were grouped according to tiers of actionability determined by matching against the TOPOGRAPH knowledge base ( https://topograph.info ) and stratified into clinically active (Tier 1-3, therapies with evidence from prospective trials), investigational (Tier 3B and 4, therapies with evidence from another cancer type, preclinical, or retrospective studies), or unmatched tier groups. To assess between-group differences in OS, hazard ratios (HR) were estimated in a time-varying Cox regression model adjusting for time to initiation of subsequent therapy. Results: This updated analysis included 3,383 pts (79% rare and less common). The median follow-up was 22.6 months (mo). For 2,065 pts who did not receive treatment after CGP, the median OS (mOS) was 8.2 mo (95% CI 7.4 to 9.0). For 1,318 pts who received ≥1 line of therapy after CGP, the mOS was 14.1 mo (13.4 to 15.2). 1,270 pts (38%) carried a genomic alteration linked to clinically active therapies (Tier 1-3). Of these, 116 (3.4%) received matched treatment after CGP, experiencing longer survival compared with 410 (32.2%) that received only unmatched therapy (mOS 21.2 v 12.8 mo, HR 0.58, 0.45 to 0.76, P 〈 0.001). Whilst receiving a matched therapy in the investigational tier group (n=133, T3B/4) did not show significant differences in outcomes (mOS 14.5 v unmatched 12.8 mo, n=536, HR 0.88, 0.72 to 1.08, p=0.24), exploratory analyses identified differences in survival for a subset of 41 pts with Switch/Sucrose Non-Fermentable complex mutations receiving matched Tier 4 therapies (mOS 30.1 v 9.6 mo, HR 0.29, 0.17 to 0.51, P 〈 0.0001). Pts receiving repurposed drugs that matched solely on biomarkers in non-cognate cancer types (Tier 3B) showed no survival difference over unmatched therapy (n=35 v 469, mOS 13.6 v 12.5 mo, HR 0.96, 0.65 to 1.41, p=0.83). Conclusions: This study provides insight into how biomarker-linked therapies can be rationally prioritised in rare and advanced cancer populations. Addressing the barriers of access to Tier 1-3 therapies may broaden the utility of genomic biomarker testing. Off-label drug repurposing without direct supporting evidence should only be undertaken in a clinical trial setting.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.1540
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Online Resource
    Genomic alterations associated with response to immune checkpoint inhibitors in rare cancers: A biomarker exploration study from the Australian Molecular Screening and Therapeutics (MoST) Program.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2594-2594
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2594-2594
    Abstract: 2594 Background: Despite immune checkpoint inhibitors (ICI) demonstrating efficacy in over 15 cancer types, evidence in most rare cancers remain scarce, reflecting the challenges of conducting prospective trials. This Australia-wide study reports real-world (RW) objective responses to ICIs targeting the programmed death-(ligand)1 (PD-1/PD-L1) pathway in a large precision oncology program, and associations between response and genomic alterations in rare cancers. Methods: This study was conducted within the framework of the MoST Program (ACTRN12616000908437), where adult patients (pts) with advanced solid tumors were screened using comprehensive genomic profiling (CGP). Only pts who received ICI after CGP were included in this analysis. The best overall response (BOR) to ICI was reported by the treating oncologist during the follow-up period. Best response was categorized as complete (CR), partial (PR), stable (SD), or progressive (PD). Two categories were defined: responders were individuals reported to have experienced CR or PR, while non-progressors were those with CR, PR, or SD. The association between tumor mutational burden (TMB) and response categories was assessed by area under the receiver operator characteristic curve (AUC). Odds ratios (OR) of specific genomic alterations associated with each category were also estimated. Results: Between Dec 2016 and Aug 2022, 4343 pts were screened; 3471 (80%) rare cancer pts, of whom 556 went on to 90 different ICI trials after undergoing CGP. In 273 pts treated with ICI where BOR was reported by the treating oncologist, the median survival was 17.3 months (95% CI 15.0 to 20.4). 13 pts (4.8%) had CR reported, including 8 pts with unapproved indications: 3 sarcomas, and 1 each, small cell carcinoma of unknown primary, adenoid cystic carcinoma, pituitary adenoma, thymoma, and pancreatic adenocarcinoma. 45 (16.5%) and 112 (41.0%) had PR and SD reported, respectively. High TMB, defined as ≥10 non-synonymous tumor mutations/megabase, was identified in 39 (14.3%) pts. TMB was associated with response (AUC 0.715, 0.630 to 0.800) and non-PD (AUC 0.600, 0.528 to 0.671) to ICI. Further exploratory analyses identified that alterations in EP300 (n = 7, OR, 9.8, 1.9 to 52), PTCH1 (n = 6, OR, 15.5, 1.7 to 141) , MSH6 and KMT2D (n = 6 each, OR, 7.7, 1.4 to 43) , and NF1 (n = 10, OR, 3.89, 1.1 to 13.9) were associated with CR/PR. Genomic ARID1A alterations (n = 18) were associated with non-PD (OR 5.16, 1.2 to 22.9), as were alterations in the SWI/SNF complex (n = 20, OR 3.64, 95% CI 1.0 to 12.8) . Conclusions: Notwithstanding their limitations, these real-world data suggest that rare cancer patients may also benefit from ICI. Further prospective investigations into pan-cancer genomic biomarkers of response are warranted. Clinical trial information: ACTRN12616000908437 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2594
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 7
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    Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 14 ( 2022-05-10), p. 1529-1541
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 14 ( 2022-05-10), p. 1529-1541
    Abstract: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.21.02112
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 8
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    Pathologic complete response and survival outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: Long-term update of NRG Oncology RTOG 9514 and 0630.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 11012-11012
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 11012-11012
    Abstract: 11012 Background: We sought to determine the prognostic significance of pathologic complete response (pCR) in soft tissue sarcoma (STS) in patients (pts) receiving neoadjuvant chemoradiotherapy (RTOG 9514) or radiotherapy (RTOG 0630) with long-term outcomes. Methods: RTOG has completed two phase II trials (RTOG 9514 and RTOG 0630) for pts with localized STS. Pts with high-grade STS ≥8 cm of extremities or body wall were enrolled to 9514 from 1997-2000 and received 3 cycles neoadjuvant chemotherapy (CT), interdigitated with RT, and 3 cycles postop CT. Pts with STS of extremities were enrolled to 0630 from 2008-2010 and received preoperative RT without CT. One pathology expert (DL) assessed pts for pCR at time of surgery without knowledge of disease outcomes. Overall and disease-free survival (OS and DFS) were calculated from the date of surgery. Pts that did not have surgery or had an amputation were excluded. Hazard ratios (HR) and p-values were estimated by multivariate Cox model stratified by study, where possible (i.e., 〉 0 events in both groups); otherwise p-values were calculated by stratified log-rank test. Results: Of 135 who had surgery, 123 were evaluable for pCR: 14/51 (27.5%) on 9514 and 14/72 (19.4%) on 0630 had pCR. With median follow-up of 〉 5 years for surviving pts, OS is 100% for pts with pCR vs. 5-year 76.5% (95% confidence interval 62.3-90.8) and 56.4% (43.3-69.5) for pts with 〈 pCR in 9514 and 0630, respectively. pCR is associated with improved OS (p = 0.01) and DFS [HR 4.91 (1.51-15.93); p = 0.008] relative to 〈 pCR. Local failure rate was 0% in pts with pCR vs. 5-year 11.7% (3.6-25.1) and 9.1% (3.3-18.5) for pts with 〈 pCR in 9514 and 0630, respectively. Leiomyosarcoma/liposarcoma/myxofibrosarcoma are associated with better OS [hazard ratio 2.24 (1.12 and 4.45)] while liposarcoma/myxofibrosarcoma are associated with better DFS [hazard ratio 2.42 (1.23-4.76)] . Conclusions: Results from this analysis have demonstrated that pCR is associated with improved survival outcomes in pts with STS treated with either neoadjuvant RT or CT-RT. pCR should be considered as a survival surrogate for future STS studies. Clinical trial information: RTOG 9514 and RTOG 0630.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.11012
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Molecular therapy selection in treatment-refractory advanced cancers: A retrospective cohort study determining the utility of TOPOGRAPH knowledge base.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3073-3073
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3073-3073
    Abstract: 3073 Background: Comprehensive genomic profiling (CGP) is increasingly used to guide therapy selection in advanced cancer patients who have exhausted standard therapy options. Here we assess the utility of Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals (TOPOGRAPH) to guide matching of drug treatments based on CGP in this setting. Methods: This study was conducted in an Australia-wide precision oncology program, the Molecular Screening and Therapeutics Study (MoST, ANZCTR registration ACTRN12616000908437). All patients with advanced cancer after exhausting standard treatments underwent CGP in 2016-2021 were stratified into cohort A (no further therapy received) and B (received ≥1 therapy after CGP). The primary outcome was overall survival (OS) estimated by the Kaplan-Meier method, using the log rank test to assess between-group differences. TOPOGRAPH matched the treatment history to the CGP results, stratified into clinically active (Tiers 1-3, T1-3), investigational (T3B/4), inactive (R2) or unmatched groups. Results: Over a median follow-up of 21.7 months (mo) for 2852 patients (75% with rare cancers, n = 2150), the median OS (mOS) from the date of CGP result was 7.0 mo (95% CI 6.4-7.6) for cohort A (n = 1562) and 15.8 mo (95% CI 14.5-16.9) for cohort B (n = 1290). In both cohorts, patients with CGP results matching any TOPOGRAPH tier (T1-4) had shorter OS compared to patients without a matching tier (A: 6.4 v 20.5 mo, hazard ratio for death [HR] 2.15, p 〈 0.001; B: 14.7 v 23.6 mo, HR 1.43, p 〈 0.001). Patients in cohort B receiving matched therapy (n=342, 27%) had a longer mOS than 948 patients who received only unmatched therapy (16.9 v 10.4 mo, HR 0.70, p 〈 0.001). For CGP results matched to T1-3, 122 patients who received a T1-3 therapy had a significantly longer mOS than those who received unmatched therapy (22.1 v 9.8 mo, HR 0.51, p 〈 0.001). For CGP results matched only to T3B/4, a trend toward longer mOS was observed in patients receiving matched therapy in T3B/4 (n = 138, 14.5 v unmatched 10.0 mo, HR 0.81, P = 0.07). In tier-matched analysis, the mOS were not significantly different between patients who received genomics matched v unmatched therapy in T3B (matching outside cognate histotypes, n = 48 v 508, 11.9 v 9.7 mo, HR 0.84, p = 0.36) and T4 (n = 32 v 134; therapy with preclinical/early clinical evidence, 17.1 v 12.2 mo, HR 0.69, p = 0.17). Conclusions: TOPOGRAPH is prognostic and likely predictive of treatment effect based on CGP, supporting its utility in guiding molecular therapy selection in patients who have exhausted standard treatment options. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3073
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Genomic targetability and survival outcomes of biliary tract cancers (BTC): A retrospective cohort study of the Australian Molecular Screening and Therapeutics (MoST) program.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4093-4093
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4093-4093
    Abstract: 4093 Background: Despite advances in therapeutic strategies, advanced BTC continue to have poor outcomes. We examined the genomic composition of these cancers and differences in clinical outcomes based on therapies (tx) received. Methods: This study included all BTC patients (pts) undergoing comprehensive genomic profiling (CGP) through an Australia-wide precision oncology program, MoST (ACTRN12616000908437). The primary outcome was overall survival (OS) measured from start of first line (1L) systemic tx. The TOPOGRAPH knowledge base was used to determine genomic actionability of alterations identified, tiered by the strength of supportive clinical evidence. Tier 1/2 are regulatory body (TGA or FDA/EMA) approved therapies in BTC; tier 3A is supported by BTC-specific clinical evidence; 3B by clinical evidence inferred from another cancer type; tier 4, pre-clinical evidence. As targeted therapies are only approved in the subsequent-line setting, a further OS analysis was performed from start of second line tx (2L). Results: Between December 2016 and August 2022, 223 pts had CGP results available: 170 cholangiocarcinoma (99 intrahepatic, 46 extrahepatic, 25 unspecified primary site) and 53 gallbladder carcinomas. Of 211 (95%) pts who received any systemic tx, median OS (mOS) was 14.6 (95% CI: 12.2—15.4) months (mo) from the start of 1L tx. Pts having received immunotherapy had a mOS of 20.7 vs 13.9 mo (HR 0.67, 0.44—1.04; p=0.07). For 198 pts with actionable findings across TOPOGRAPH tiers, receipt of matched tx (n=37) was associated with a significantly longer mOS of 21.4 (15.0—31.8) compared with receipt of unmatched tx (n=161), mOS 12.6 mo (11.5C15.2, hazard ratio for death, HR 0.46, p 〈 0.001). Pts with tier 1-3 actionable alterations who received matched tx had a median OS of 30.5 mo (95% CI: 18.8 - not reached, NR) compared with 12.1 mo (9.8—16.1, HR 0.39, p=0.02) if only unmatched tx received. Receipt of tier 3B/4 matched tx (n=13) only showed a trend towards longer survival, 15.6 mo vs unmatched 14.0 mo (HR 0.60, p=0.16). For 149 pts who received 〉 1 line of systemic tx: 35 matched and 103 unmatched alone, mOS (measured from 2L tx) was 11.3 (5.7-28.4) compared with 8.3 mo (6.1-10.6) respectively (HR 0.67, p=0.10). A significantly longer OS was seen for matched vs unmatched, in pts receiving tier 1-3 tx: mOS 19.0 mo vs 8.3 mo (HR 0.43, p=0.04), but not for tier 3B/4, mOS 5.6 vs 6.7 mo HR 1.31, p=0.48. The most common genomic alterations were in TP53 (86, 39%), KRAS (59, 26%), CDKN2A (43, 19%), and ARID1A (29, 13%), while actionable findings commonly involved IDH1 (26, 12%), FGFR2 (20, 9%), ERBB2 (14, 6%), and BRAF (11, 5%). Conclusions: Receipt of genomically matched tx, particularly those supported by TOPOGRAPH tiers 1-3 evidence was associated with longer OS for pts with advanced BTC. Our results support the greater use of CGP in the management of these pts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4093
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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