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  • 11
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    Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. 93-93
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 93-93
    Abstract: 93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P 〈 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R] ) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.093
    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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  • 12
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    A phase 1b/2 trial of the PLK1 inhibitor onvansertib in combination with FOLFIRI-bev in 2L treatment of KRAS-mutated (mKRAS) metastatic colorectal carcinoma (mCRC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. 100-100
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 100-100
    Abstract: 100 Background: CRC is a common cancer world-wide, accounting for ̃10% of cancer cases and mortality. Treatment options are limited, and survival is poor for pts with advanced disease, particularly those with mKRAS. After failure of 1L treatment for mCRC, regardless of KRAS mutation status, the ORR for FOLFIRI-bev is 5-13%, with PFS 4-6 mos, and OS 10-12 mos. Onvansertib is a highly selective, ATP-competitive, orally bioavailable PLK1 inhibitor that is synergistic with irinotecan and with 5FU in xenograft models of mKRAS CRC. We present preliminary safety, efficacy, and biomarker data from an ongoing Ph1b/2 trial of onvansertib + FOLFIRI-bev in pts with mKRAS mCRC progressing after 1L treatment with fluoropyrimidine + oxaliplatin, +/- bev. Methods: Pts with mCRC with a KRAS mutation detected by a CLIA-certified lab were eligible. In the Ph1b portion of the study, onvansertib was given on a 3+3 dose escalation at 12, 15 or 18 mg/m 2 on days 1-5 and 15-19 of each 28-day cycle in combination with FOLFIRI-bev. The MTD was 15 mg/m 2 and was chosen as the RP2D. The primary endpoint for the Ph2 was ORR, and radiographic response was assessed every 8 wks per RECIST v1.1. Safety was evaluated continuously, and AEs were recorded using CTCAE v5.0. Baseline and post-treatment blood samples were collected for biomarker analyses, including mutant allele frequency (MAF) of the pt’s known KRAS mutation. Results: As of 16Sep2021, a total of 50 pts had been treated: 18 on the Ph1b and 32 on the Ph2, including 35 pts at the RP2D, and median follow up was 4.7 mos (range 0.4-18). Of the 50 pts, 26 remain on treatment, as do 24 of 35 RP2D pts. The combination was well-tolerated: fatigue, neutropenia, and nausea were the most common treatment-emergent adverse events (TEAE) and were generally low-grade. Neutropenia was managed by removing the 5FU bolus from subsequent cycles of FOLFIRI and adding growth factor. Of the 50 pts, 44 were evaluable for efficacy, including 31 of 35 RP2D pts. ORR was 36% for the total group (1CR and 15 PR in 44 pts) and 35% for the RP2D group (1 CR and 10 PR in 31 pts). First responses were seen between 2 and 6 months after the start of therapy. Responses were observed across different KRAS variants. Pts achieving a CR or PR showed the greatest decreases in plasma MAF after the first cycle of therapy. Of the 50 pts, 24 pts have discontinued for the following reasons: progressive disease (13), toxicity (4), patient decision (4), proceeding to potentially curative surgery or other localized therapy (3). Conclusions: The combination of onvansertib with FOLFIRI-bev was well tolerated: observed TEAEs have been generally low-grade and manageable. The combination has demonstrated a promising ORR in 2L treatment of mCRC pts harboring various KRAS mutations, and efficacy was correlated with early changes in plasma mKRAS. Updated safety, efficacy, and biomarker analyses will be presented. Clinical trial information: NCT03829410.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.100
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 13
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    Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4006-4006
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4006-4006
    Abstract: 4006 Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m 2 + 5-FU 2400 mg/m 2 + LV 400 mg/m 2 + oxaliplatin 60 mg/m 2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m 2 + gemcitabine 1000 mg/m 2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4006
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 14
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    Molecular and clinical characteristics of patients with KRAS mutated pancreatic ductal adenocarcinoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e16259-e16259
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16259-e16259
    Abstract: e16259 Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e16259
    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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  • 15
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    Clinical synergy of universal paired tumor genomic and germline sequencing in an unselected, pan-cancer cohort of patients: Greater than the sum of the parts.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e22537-e22537
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e22537-e22537
    Abstract: e22537 Background: Germline and tumor next-generation sequencing (NGS) are complementary tests whose benefit in capturing patients (pts) potentially eligible for precision therapies is maximized when the tests are paired, as qualifying pathogenic variants (PVs) are missed if either test was done in isolation (Lincoln et al. 2020). Germline NGS has the additional benefit of informing prevention through surveillance and cascade testing. We highlight the benefits of a universal approach to concurrent testing in a subset of the previously reported cohort of pan-cancer pts who underwent universal germline NGS (Samadder et al. 2020). Methods: Unselected pts with solid tumors underwent an 80+ gene germline panel and 315+ gene tumor panel. Variants in genes unique to the germline or tumor panels, including microsatellite instability (MSI) and tumor mutation burden (TMB), were also evaluated. Results: 104 pts [81.7% White, non-Hispanic, 71.2% male] with 23 cancer types [28% colorectal, 13% lung, 11% prostate, 49% other] were included. Five (5%) pts had no actionable tumor alterations or germline variants identified (Table). 18 pts (17%) had 19 pathogenic germline variants (PGVs) identified, 11 (58%) of which were detected on tumor NGS (Table). 92 pts had 〉 1 tumor alteration identified, of which 12% were confirmed as PGVs (Table). Notably, tumor NGS revealed 81 pts (78%) pts with biomarkers that would could not have been identified with germline testing alone, such as variants in genes not on germline panel (80) or MSI-high (4), or TMB-high (21) status of the tumor. Conclusions: Germline and tumor NGS are complementary tests that often detect different actionable alterations. There is value in confirming both the presence and absence of somatic variants in the germline in order to make appropriate clinical recommendations for the patient and their family members. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e22537
    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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  • 16
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    SEAMARK: Randomized phase 2 study of pembrolizumab + encorafenib + cetuximab vs pembrolizumab alone for first-line treatment of BRAF V600E–mutant microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS268-TPS268
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. TPS268-TPS268
    Abstract: TPS268 Background: Among patients with MSI-H/dMMR CRC, BRAF mutations occur in approximately 30%. MSI-H/dMMR and BRAF mutations are both associated with poor prognosis; in patients who have both biomarkers, poor prognosis is thought to be driven by the BRAF mutation. Pembrolizumab is indicated for the treatment of patients with MSI-H/dMMR unresectable or metastatic CRC (mCRC). The BRAF inhibitor encorafenib, in combination with cetuximab, an anti-EGFR antibody, is indicated for previously treated patients with BRAF V600E-mutant mCRC. Currently, there are no first-line treatment options indicated specifically for patients with both MSI-H/dMMR and BRAF V600E-mutant mCRC. To assess the safety and efficacy of combining pembrolizumab with encorafenib + cetuximab, the SEAMARK study will evaluate this combination vs pembrolizumab alone in patients with previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC. Methods: SEAMARK (NCT05217446) is an open-label, multicenter, randomized, phase 2 study. Approximately 104 patients (randomized 1:1; stratified by Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 vs 1) will receive either pembrolizumab + encorafenib + cetuximab or pembrolizumab. Enrolled patients must be aged ≥16 or ≥18 years (per country-specific regulations) and have previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC; measurable disease (Response Evaluation Criteria in Solid Tumors 1.1); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients who received prior treatment with BRAF/EGFR inhibitors or immune checkpoint inhibitors, or who have brain metastases (unless radiologically stable) or RAS mutation (or unknown RAS status), will be excluded. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment started in July 2022. Clinical trial information: NCT05217446 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.TPS268
    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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  • 17
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    Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): A phase 2 basket study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4007-4007
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4007-4007
    Abstract: 4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) pe r investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4007
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 18
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    HER2 testing in colorectal cancer: Concordance analysis between breast and gastric scoring algorithms from the MOUNTAINEER trial.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. 198-198
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. 198-198
    Abstract: 198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.198
    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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  • 19
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    Outcome of receiving lenvatinib following immunotherapy in patients with advanced hepatocellular carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 4_suppl ( 2023-02-01), p. 507-507
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 4_suppl ( 2023-02-01), p. 507-507
    Abstract: 507 Background: Lenvatinib, a multikinase inhibitor, is an FDA approved treatment for advanced hepatocellular carcinoma (HCC) in the first line setting. Atezolizumab and bevacizumab are considered new standard of care as first line therapy after results of the IMBrave 150 trial. Currently, we do not have data to suggest any second-line treatment after administration of immunotherapy. We describe the clinical outcomes in patients with advanced HCC who received lenvatinib following treatment with immunotherapy. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the intuitional review board. The primary outcomes were overall survival (OS) and progression free survival (PFS). Results: We identified 53 patients with advanced HCC who received lenvatinib following immunotherapy. Most patients (83%) were male. Median age at start of lenvatinib was 67 years old. Forty-two (79%) patients had a Child-Pugh score of A at diagnosis while 30 (58%) patients were still Child-Pugh A at time of lenvatinib initiation. Risk factors for HCC included Hep C (43%), alcohol use (34%), NASH (15%) and hepatitis B (7%). Forty-five (85%) patients received lenvatinib in the 2 nd line and 8 (15%) patients received it as third line or later. At time of data extraction, 38 (72%) patients had died. Median PFS was 4 months (95% CI: 3 – 6) and median OS from time of lenvatinib initiation was 13 months (95% CI: 6 – 24). The most common adverse events of any grade included fatigue (53%), hypertension (37%), AST elevation (30%), anorexia (28%), bilirubin elevation (25%) and diarrhea (25%). Twenty-one (40%) patients experienced grade 3 or higher adverse events including hypertension (25%), confusion (6%), acute kidney injury (2%), hyperkalemia (2%), ALT elevation (2%), proteinuria (2%), arthralgia (2%), heart failure (2%), AST elevation (2%), bilirubin elevation (2%), palmar-plantar erythrodysesthesia (2%), oral mucositis (2%), weight loss (2%), hypothyroidism (2%), anorexia (2%), fatigue (2%) and diarrhea (2%). Seven patients stopped treatment due to adverse events: 1 for hypertension, 2 for confusion, 1 for heart failure, 2 for fatigue, and 1 for elevated bilirubin. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. We found that median OS was 13 months in patients who received lenvatinib after immunotherapy which is comparable to survival in other studies when used as first line therapy. Our experience demonstrates that patients may benefit from treatment with lenvatinib following initial progression on immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.4_suppl.507
    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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    A randomized phase II trial of MEK and CDK4/6 inhibitors vesus tipiracil/trifluridine (TAS-102) in metastatic KRAS/NRAS mutant (mut) colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4_suppl ( 2022-02-01), p. 116-116
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4_suppl ( 2022-02-01), p. 116-116
    Abstract: 116 Background: Constitutively activating KRAS or NRAS muts occur in ̃50% of CRC, increasing RAF-MEK-ERK signaling and causing overexpression of cyclin D1, which binds to cyclin dependent kinase 4/6 (CDK4/6) to drive cell cycle progression. Combination MEK and CDK4/6 inhibitors caused tumor regression in patient-derived xenografts of KRAS mut CRC. We hypothesized that binimetinib and palbociclib (B+P) would improve progression-free survival (PFS) compared to TAS-102 in refractory KRAS/NRAS mut mCRC. Methods: ACCRU-GI-1618 was a multicenter, randomized phase II clinical trial (NCT03981614). Key inclusion criteria were KRAS/NRAS mut mCRC, with prior fluoropyrimidine/ oxaliplatin/ irinotecan/ anti-VEGF therapy. There was a 6-patient safety run-in with binimetinib 30 mg po BID D1-28 and palbociclib 100 mg po daily D1-21. After, patients were randomized 1:1 to B+P vs TAS-102 (stratified by KRAS mut type and prior regorafenib use), with optional crossover at progression. The primary endpoint was PFS; 73 PFS events (from a sample size of 112) provided 90% power to detect improvement of PFS (hazard ratio = 0.5, i.e. median PFS of 2 vs. 4 months) with 1-sided α = 0.05. A prespecified interim analysis for futility was planned after 37 PFS events were observed, with completion of accrual if 1-sided stratified log-rank p-value 〈 0.551. Hazard ratios (HR) and 95% confidence intervals (CI) are estimated by stratified Cox proportional hazards models. Results: After the safety run-in, 93 patients at 6 sites were randomized; 82 (41 B+P, 41 TAS-102) comprise the primary analysis population (eligible, consented, and started treatment). In this population, median age was 52 years, 50% female, 68% left-sided, 79% with KRAS codon 12/13 mut, 12% with prior regorafenib. Enrollment was halted at interim analysis as the futility boundary was crossed (1-sided p = 0.67). At final analysis, 68 subjects had a PFS event (34 in each arm). Median PFS was 2.1 mo (95% CI 2.0-3.0) with B+P vs 2.1 mo (2.0-2.4) with TAS-102; HR 0.86 (0.52-1.44). 4-mo PFS rate was 22.2% (11.9-41.6) with B+P vs 10.6% (3.8-30.0) with TAS-102. With 37 OS events (14 in B+P arm), median OS was 7.7 mo (5.1-NE) with B+P vs 6.6 mo (4.8-8.9) with TAS-102; HR 0.77 (95% CI 0.39-1.51). TAS-102 had greater grade 3-4 hematologic AEs (46% vs 22%), and B+P had more grade 3-4 non-hematologic AEs (47% vs 32%). Grade 3-4 AEs more common with B+P were fatigue (8% vs 0%), oral mucositis (6% vs 0%), and nausea (4% vs 2%). Though 63% of patients on B+P had acneiform rash, only 2% was grade 3-4. Grade 1-2 diarrhea occurred in 35% of B+P and 24% of TAS-102 patients. No new safety signal was observed. Conclusions: B+P did not significantly improve median PFS or OS compared to TAS-102 in KRAS/NRAS mut mCRC. Subgroup analyses and translational studies are ongoing to determine which subgroups may be more likely to attain 4-mo PFS or identify mechanisms of resistance. Clinical trial information: NCT03981614.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.4_suppl.116
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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