Showing papers by "Salvatore Siena published in 2023"

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study.

Abstract: Background HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. Methods MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. Findings Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47–64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7–49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. Interpretation Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. Funding Seagen and Merck & Co. HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47–64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7–49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer.

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer

Abstract: DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results.

Abstract: LBA3000 Background: T-DXd is an antibody drug conjugate targeting HER2 and is approved in HER2-expressing breast (BC) and gastric (GC) cancers. HER2 expression is prevalent in other solid tumors. The efficacy of current treatments (Tx) in these populations, including studies with HER2-directed Tx, is modest, revealing a significant unmet medical need. Clinically meaningful activity of T-DXd was seen in HER2-expressing tumors in a phase 1 study (NCT02564900). Methods: DP-02 (NCT04482309) is an open-label phase 2 study of T-DXd 5.4 mg/kg q3w in pts with HER2-expressing (immunohistochemistry [IHC] 3+ or IHC 2+ by local or central testing) locally advanced or metastatic disease that progressed after ≥1 systemic Tx or that has no Tx options. Cohorts with biliary tract (BTC), bladder (URO), cervical (CC), endometrial (EC), ovarian (OC), pancreatic (PC), or other tumors (excluding BC, GC, colorectal cancer, and non-small cell lung cancer) were enrolled. Efficacy and safety were analyzed in all pts who received ≥1 dose of T-DXd. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate, progression-free and overall survival, and safety. Results: At data cutoff (16 Nov 2022; median follow-up, 9.7 mo), 267 pts had been treated (median, 2 prior lines of Tx [range, 0-13]); 75 pts were IHC 3+ and 125 were IHC 2+ by central testing. In all 267 pts, the ORR was 37.1% and median DOR (mDOR) was 11.8 mo; in pts with IHC 3+ expression, the ORR was 61.3% and mDOR was 22.1 mo. ORR per cohort is shown in all pts and those with centrally confirmed HER2 IHC 3+ or IHC 2+ expression. Grade (G) ≥3 adverse events (AEs) occurred in 58.4% of pts; 11.6% discontinued Tx due to AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 18 pts (6.7% [G1, n=6; G2, n=11; G5, n=1]). Conclusions: This is the first tumor-agnostic global study of T-DXd in a broad range of HER2-expressing solid tumors. T-DXd showed encouraging ORR, particularly in pts with IHC 3+ expression, durable clinical benefit, and a manageable safety profile in this heavily pretreated population. These interim results show T-DXd to be a potential new Tx option for pts with HER2-expressing solid tumors. Clinical trial information: NCT04482309 . [Table: see text]

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress.

Abstract: TPS261 Background: Current standard of care (SOC) for treatment (tx) of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, w/ or w/o a VEGF- or EGFR-inhibitor. HER2 is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%-5% of patients (pts) w/ mCRC; the rate of HER2 amplification can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC), a highly selective, HER2-directed tyrosine kinase inhibitor, is approved in multiple regions for HER2+ metastatic breast cancer and is being investigated in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in pts w/ tx refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity (confirmed ORR of 38.1% and median DOR of 12.4 months) and demonstrated TUC + Tras was well tolerated with a low discontinuation rate (5.8%) and no deaths due to AEs. MOUNTAINEER-03 will further investigate TUC in combo w/ mFOLFOX and Tras in pts w/ RAS wild-type, HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open label, randomized, phase 3 study for 1L tx of HER2+ and RAS wild-type mCRC. Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab). HER2 status is determined centrally w/ tissue based HER2 immunohistochemistry and in situ hybridization assays. Eligible pts must not have received prior tx in the metastatic setting but may have received adjuvant tx if completed > 6 months prior to enrollment. Pts must be ≥18 years of age w/ an ECOG performance status of ≤1 and RAS wild-type mCRC. Pts w/ treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). Primary endpoint is progression-free survival per RECIST v1.1, assessed by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate per RECIST v1.1 assessed by BICR. Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651 .

Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity

Abstract: Abstract Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICI), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, that could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

HER2 testing in the MOUNTAINEER trial: Analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS.

Abstract: 3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]

Data from Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2<sup>+</sup> Malignancies

Abstract: <div>Abstract<p>Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll‐like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2⁺ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2⁺ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.</p></div>

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and modified FOLFOX6 as first line treatment in HER2+ metastatic colorectal cancer.

Abstract: TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

Abstract CT029: Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation

Abstract: Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020). Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 11 patients (38%). Five patients (17%) experienced at least one serious AE, none of which were treatment-related (including 2 patients who died of CRC progression during the safety follow-up). AEs led to GDC-6036 modifications (interruptions and/or reductions) in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued due to AEs. Eleven patients discontinued from study treatment (10 due to disease progression and 1 due to physician’s discretion). The PK profile of GDC-6036 (400 mg once a day) was similar in combination with cetuximab when compared with single-agent. A partial response was achieved in 66% (19/29) of patients, with a confirmed ORR of 62% (18/29 patients). Conclusions: GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC. Citation Format: Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller, Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT029.

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.

Abstract: 3501 Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831 . [Table: see text]

HER2 testing in colorectal cancer: Concordance analysis between breast and gastric scoring algorithms from the MOUNTAINEER trial.

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]

Circulating tumor DNA to drive treatment in metastatic colorectal cancer.

Abstract: In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Since the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through the analysis of circulating tumor DNA (ctDNA), has proven safe and effective as a complementary method to address cancer evolution while overcoming the limitations of tissue biopsy. Even though data are accumulating regarding the potential for ctDNA-guided treatments applied to targeted agents, still major gaps in knowledge exist as for their application to different areas of the continuum of care. In this review, we recapitulate how ctDNA information could be exploited to drive different targeted treatment strategies in mCRC patients, by refining molecular selection before treatment by addressing tumor heterogeneity beyond tumor tissue biopsy; longitudinally monitoring early-tumor response and resistance mechanisms to targeted agents, potentially leading to tailored, molecular-driven, therapeutic options; guiding the molecular triage towards rechallenge strategies with anti-EGFR agents suggesting the best time for retreatment; and providing opportunities for an "enhanced rechallenge" through additional treatments or combos aimed at overcoming acquired resistance. Besides, we discuss future perspectives concerning the potential role of ctDNA to fine-tune investigational strategies such as immuno-oncology.

Sotorasib (Soto) plus panitumumab (Pmab) and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 phase 1b safety and efficacy.

Abstract: 3513 Background: Soto, a KRASG12C inhibitor, had a 9.7% objective response rate (ORR) as monotherapy for chemorefractory patients (pts) with KRAS G12C-mutated mCRC. When combined with Pmab, a monoclonal anti-EGFR antibody, ORR increased to 30%, supporting the model that the doublet mitigates Soto-related feedback reactivation of the RAS-MAPK pathway and accumulation of activated EGFR. We hypothesize that Soto plus Pmab and FOLFIRI will further enhance Soto efficacy while maintaining a manageable safety profile. We report the first results for a KRASG12C inhibitor combined with an EGFR inhibitor and chemotherapy in pts with prior mCRC treatment. Methods: Pts included dose exploration and expansion cohorts from CodeBreaK 101 subprotocol H (NCT04185883) who received Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and standard-dose FOLFIRI (IV Q2W). Key eligibility criteria were KRAS G12C-mutated mCRC and ≥1 prior treatment for metastatic disease. Pts in dose expansion were KRASG12C inhibitor-naïve. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). Results: As of November 30, 2022, 33 pts (median age: 53 years; 48% female) were treated (6 in dose exploration, 27 in dose expansion). Median prior lines of systemic therapy was 2 (range: 1-6), with 33% and 67% of pts receiving 1 or ≥ 2 prior lines, respectively; 97% had prior fluoropyrimidine and 73% had prior irinotecan. Two pts in dose exploration received prior Soto. None of the 6 pts in dose level 1 of dose exploration had dose limiting toxicities (DLTs) during DLT evaluation (first 28 days), and Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and FOLFIRI (IV Q2W) was the recommended phase 2 dose. Treatment-related adverse events (TRAEs) of any grade occurred in 32 (97.0%) pts; 1 pt discontinued the full regimen due to grade 3 ALT increase. Fifteen (45.5%) had grade ≥ 3 TRAEs (most commonly dermatologic; n = 5). There were no fatal TRAEs. Safety findings were consistent with known profiles of Soto, Pmab, and FOLFIRI. No clinically meaningful PK interaction was observed between Soto and irinotecan. Of 31 pts evaluable for response, confirmed ORR (all partial responses) was 58.1% (95% CI: 39.1, 75.5). The 2 pts with prior Soto achieved partial response (n = 1) and stable disease (n = 1). Disease control rate was 93.5% (95% CI: 78.6, 99.2). With median follow-up of 5.7 and 7.4 months, respectively, progression-free and overall survival data are not yet mature. Fully enrolled data will be presented. Conclusions: In the first ever data set for this novel combination, Soto plus Pmab and FOLFIRI showed promising safety and efficacy in pretreated KRAS G12C-mutated mCRC, with a confirmed ORR of 58.1%. Adverse events were manageable and consistent with the expected safety profile of the drugs used, and there was no clinically meaningful Soto and irinotecan PK interaction. Clinical trial information: NCT04185883 .

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Abstract: PURPOSE Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. PATIENTS AND METHODS KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. RESULTS KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. CONCLUSION Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

Corrigendum: Case report: MAP2K1 K57N mutation is associated with primary resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer

Abstract: [This corrects the article DOI: 10.3389/fonc.2022.1030232.].

High-dose vitamin C to enhance neoadjuvant immune checkpoint therapy in mismatch repair proficient colon cancer: The ALFEO pilot study.

Abstract: TPS2675 Background: Most colon cancer (CC) patients can be treated with upfront curative surgery; however, relapse often occurs and the disease becomes deadly. Neoadjuvant chemotherapy does not jeopardize timing or quality of surgery and enhances relapse-free outcomes in proficient mismatch-repair (pMMR) CC (Morton et al, J Clin Oncol 2023). In the same setting, the use of immune checkpoint inhibitors (ICIs) with a single dose of ipilimumab (Ipi) and two doses of nivolumab (Nivo) proved to be feasible without delaying surgery and resulting in 23% major pathological responses (mPR) (Chalabi et al, ASCO 2022). We have previously shown that high dose vitamin C (HDVitC) triggers tumor infiltration and activation of CD8+ T cells in mouse tumors, enhancing efficacy of ICIs in pMMR CC preclinical models (Magrì et al, Sci Transl Med 2020). Methods: ALFEO is an open-label pilot trial of neoadjuvant CC treatment to test whether HDVitC can enhance the efficacy of ICIs in this setting. Main inclusion criteria are pMMR CC stage cT4N0/TxN1-2/[cM1 liver-limited disease with favorable oncological criteria candidate for upfront surgery on both T and M after multidisciplinary team evaluation]. Patients will receive Nivo i.v. 3 mg/kg D1 and D15, Ipi i.v. 1 mg/kg D 1 and VitC 70 g/ m2 D1-3 and 15-17. Tumor assessment will be performed at D21-28, followed by surgery within D28. Primary objective is activity of Nivo/Ipi + HDVitC; secondary objective is safety; exploratory objectives are correlation between efficacy and pharmacodynamic including tumor microenvironment changes. Primary endpoint is mPR rate. Considering the proof-of-principle nature of the trial, a design with a boundary for early stopping (both futility/utility and toxicity) and a fixed maximum sample size of 24 patients has been chosen. mPR for the Ipi/Nivo has been set at 23% (H0), while H1 at 75%. A Bayesian hypothesis test-based design (Zhou et al, Pharm Stat 2021) will be used for decision-making. Su. Clinical trial information: ECTR2022-502101-15-00 .

Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report

Abstract: Cancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent.A 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy.Even considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Abstract: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Young-onset colorectal cancer: treatment-related nausea, vomiting and diarrhoea

Abstract: Objectives Early-onset colorectal cancer (EO-CRC) incidence is increasing, raising a clinical challenge. Clinicians tend to treat EO-CRC patients with more intensive regimens despite the lack of survival benefits, based on an age-related bias. Limited evidence is available regarding treatment-related toxicities in this peculiar subset of patients. Methods We performed a literature search in MEDLINE/PubMed, EMBASE and Scopus, looking for reporting of nausea, vomiting and diarrhoea occurring in patients with EO-CRC, defined by age lower than 50 years old at initial diagnosis, while receiving anticancer treatment. Results 2318 records were screened and 9 full-text articles were considered eligible for inclusion for a total of 59 783 patients (of whom 8681 EO-CRC patients). We found nausea and vomiting occurring at higher incidence among EO-CRC compared with older patients, while no difference was reported as for diarrhoea. Peritoneal involvement, age younger than 40, female gender, suboptimal adherence to guidelines and oxaliplatin might represent potential risk factors for increased nausea and vomiting in patients with EO-CRC. Conclusion EO-CRC patients experience more nausea and vomiting but equal or less diarrhoea compared with older patients. Adherence to clinical guidelines is recommended, and more data are warranted to assess if an enhanced antiemetic approach might be required, particularly in case of specific risk factors.