514
Background: HER2low, defined as immunohistochemical (IHC) 1+ or 2+ without HER2 gene amplification, predicted improved progression free and overall survival with trastuzumab deruxtecan (TDXd) ...compared to chemotherapy in patients (pts) with metastatic breast cancer in Destiny Breast04. Controversy exists regarding the correlation of HER2low with molecular subtypes and outcome. We evaluated these associations in the neoadjuvant ISPY2 trial. Methods: We investigated HER2 IHC class in pts with clinically HER2-negative breast cancer (BC) enrolled in the first 10 arms of ISPY2. To explore the biology of HER2low, we used Fisher’s exact test to assess association of IHC class (0 vs 1+ or 2+) with Response Predictive Subtypes-5 (RPS-5; based on immune, DNA repair damage (DRD), HER2, and luminal markers; PMID: 35623341), SET index endocrine responsiveness, and Mammaprint high1 (MP1) vs high2 (MP2). Association with pathologic complete response (pCR) was assessed using Fisher’s exact test, and association with distant recurrence free survival (DRFS) was assessed using Cox Proportional Hazards modeling. Results: Of 742 HER2negative pts enrolled in the first 10 arms of ISPY2, local HER2 IHC is available for 585; 299 hormone receptor + (HR+) and 286 triple negative (TN). 63% of pts are HER2low, with HER2low status more frequent in HR+ (71%) compared to TN BC (55%; OR = 1.97; p = 0.00011). There was no clear relationship between HER2low IHC and RPS-5 subtypes or endocrine sensitivity measured by the SET index. There was no significant association of HER2low with pCR overall or within treatment arms (p > 0.05); this was true for TN and HR+ subsets. 562 pts with HER2negative disease have distant recurrence free survival (DRFS) data with a median follow-up of 4.23 yrs. Pts with pCR had excellent outcome (5yr DRFS > 94%), with no impact from HER2low vs 0 status. For pts with nonpCR, after adjusting for HR+ status, the DRFS hazard ratio for HER2low vs 0 status is not significant 0.68(0.46-1.02). Within HR+, HER2low is found in > 70% for both SET low and high. HR+/MP1 pts (with generally low pCR rates) are significantly more likely to be HER2low (75%; (172/219)) compared to HR+/MP2 (61%; (49/80)) (OR: 1.79; Fisher p = 0.044). Importantly, 70% of HER2-Immune-/DRD- (78% HR+ and 56% TN), a subtype with low response to all ISPY2-tested agents, are HER2Low. Conclusions: In ISPY2 which enrolls patients with MP high risk BC, HER2low by IHC was frequent and higher in HR+ than TN disease. There was no clear association with molecular markers, pCR or DRFS. The frequency of HER2low in the immune-/DRD- subtype raises the potential for exploring T-DXd in this high risk, low-response setting. Clinical trial information: NCT01042379 .
TPS1119
Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, ...and everolimus + exemestane are the current approved second-line regimens. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations (m) driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1-mut status. While Phase I SERD combination data in the post-CDK4/6i setting are encouraging, there are no randomized combination data. Combining giredestrant and everolimus may improve outcomes after CDK4/6is and in pts with ESR1m tumors. Methods: evERA BC (NCT05306340), a Phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs. exemestane + everolimus in pts with ER+, HER2– LA/mBC who had previous treatment with a CDK4/6i and ET in the LA/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD), or exemestane (25 mg) + everolimus (10 mg) PO QD. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment. Eligibility: Female/male pts ≥ 18 years with ER+, HER2– LA/mBC and disease progression ≥ 6 months (mo) after initiating ET + CDK4/6i in the LA/mBC setting (and ≥ 4 mo on most recent ET, if ET + CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 mo of exposure to combination adjuvant ET (≥ 12 mo) + CDK4/6i (≥ 6 mo), and available blood sample for circulating tumor DNA central testing for ESR1m status. Men and pre-/perimenopausal women will receive a LHRH. Co-primary endpoints: Investigator-assessed progression-free survival (per RECIST v1.1) in the intent-to-treat and ESR1m populations. Secondary endpoints: Overall survival; objective response rate; duration of response; clinical benefit rate; pt-reported outcomes; safety; pharmacokinetics. Co-primary endpoint analyses will use a two-sided stratified log-rank test at an overall 0.05 significance level. An independent data monitoring committee will be in place for safety. Target enrollment is 320 pts, and this study is currently recruiting. Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340 .
TPS1118
Background: Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that ...may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (palbo) and fulvestrant (FUL). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1 (NCT05501886). Methods: This Phase 3 multinational clinical trial will evaluate geda and FULwith or without palboin patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, palbo, and FUL), Arm B (geda and FUL), or Arm C (FUL). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival, safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. The trial is open for enrollment. Clinical trial information: NCT05501886 .
1091
Background: Talimogene laherparepvec (TVEC) is a modified oncolytic herpes simplex 1 (HSV1) virus that may enhance tumor immune infiltration and is currently FDA-approved for the treatment of ...unresectable cutaneous, subcutaneous, and nodal melanoma. Anti-tumor responses have been seen both locally and systemically, and an abscopal systemic effect has been described in distant organ metastases. Methods: In this single arm, open label Phase 1b study, patients received intra-tumoral TVEC (first dose 10
6
PFU/mL followed by 10
8
PFU/mL q2-3 weeks; volume based on tumor size up to max 4mL) in combination with CT (gemcitabine/carboplatin GC, nab-paclitaxel Nab-P, or paclitaxel P) or ET at the discretion of the treating physician. All patients had at least one 1 cm lesion that was injectable at the bedside. The primary endpoint was safety and tolerability. The secondary endpoint was response by RECIST 1.1. Blood and tissue-based immune correlates including injected and neighboring non-injected lesions were evaluated. Results: 19 pts were enrolled on this study (2/5/20 – 1/25/23) and evaluable for toxicity with 1 pt non-evaluable for efficacy due to early discontinuation. Median age was 52.1 years. Nine pts (47%) had HR+/HER2- BC and 10 pts (53%) had TNBC. Injected lesions included intact subcutaneous skin nodules (7), non-fungating breast or chest wall lesions (12), and fungating breast or chest wall lesions (9). Pts had a median of 3 prior lines of systemic therapy in the metastatic setting (range 0-9). 13 pts (74%) had visceral metastases. Pts received TVEC with the following treatment partners: GC (n=8, 42%), Nab-P (n=7, 37%), P (n=2, 11%), ET (n=2, 10%). Median treatment duration was 11.6 weeks (range 1.0-45.0 weeks). Grade 3-4 treatment-related adverse events included neutropenia (n=5, 26%), anemia (n=1, 5%), thrombocytopenia (n=1, 5%), and injection site skin ulceration (n=1, 5%). Three pts (16%) had Grade 1-2 injection site skin ulceration. Response per RECIST 1.1 was evaluated in 16 pts (2 pts had rapid progression prior to first response evaluation): PR (n=2, 13%), SD (n=5, 31%), and PD (n=9, 56%). Disease response at the site of TVEC injection was clinically evaluated in 18 pts, with response rates (RR) as follows: partial response (PR) (n=11, 61%), stable disease (SD) (n=4, 22%), and progressive disease (PD) (n=3, 17%). Mass cytometry (CyTOF) analysis demonstrated a decrease in HLA-DR expression circulating lymphocytes and in TIM3 expression across multiple cell types in responders vs. non-responders; updated correlative analyses will be presented. Conclusions: The addition of intra-tumoral TVEC to CT or ET is safe and tolerable in pts with advanced BC. This treatment induces changes in circulating immune responses. Clinical trial information: NCT03554044 .
TPS1134
Background: While PARP inhibitors are approved for germline BRCA1/2 mutant MBC, and are shown to improve both patient quality of life and progression-free survival (PFS), as a well-tolerated ...oral targeted therapy, their utility is limited as germline BRCA1/2 mutations are present in 5-10% of breast cancer. We hypothesize that somatic BRCA1/2 mutations may also respond to PARP inhibitors. We have demonstrated that somatic BRCA1/2 mutations can be identified by cell-free DNA and tumor tissue genotyping assays in patients who are not known germline BRCA1/2 carriers, and some of these are pathogenic. Using a circulating tumor cell culture model developed from a patient with a pathogenic somatic BRCA1 mutation, we have shown that a PARP inhibitor can induce cell growth inhibition paralleling germline BRCA1/2 mutant lines. In this trial, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may help expand the number of patients with MBC who benefit from a PARP inhibitor. Methods: In this phase II investigator-initiated clinical trial, 30 patients with MBC harboring somatic BRCA1/2 mutations identified via a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are evaluated for pathogenicity using validated genomic databases such as ClinVar by genetic counselors prior to enrollment. Patients may have metastatic triple-negative or hormone receptor positive (HR+)/HER2- breast cancer progressing on 1 prior therapy, and should not be known germline BRCA1/2 carriers. Any number of prior therapies are allowed but patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day (a PARP inhibitor with high potency) until disease progression. Imaging (CT chest abdomen and pelvis as well as bone scan) occurs at baseline and every 3 months for disease assessment. The primary endpoint is progression-free survival (RECIST 1.1). This study has 81% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Key secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Correlative studies include collecting cell-free DNA at baseline and monthly to identify the emergence of resistance mutations and impact of BRCA1/2 reversion mutations and mutant allele fraction on response, and evaluating the Cancer Risk B (CR-B) assay, a novel method that identifies double-strand break repair mutations in circulating blood cells. The study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, Emory, University of California San Francisco, and Northwestern, and pending activation at Vanderbilt and Cornell, with 11 patients enrolled as of 2/2023. Clinical trial information: NCT03990896 .
TPS619
Background: TNBC has an aggressive disease course with poor prognosis for pts with residual disease (RD) after NAT. In Ph 3 KEYNOTE-522, pts treated with polychemotherapy + the immune ...checkpoint inhibitor (ICI) pembro for ~1 year only had a 3-year event-free survival of 85% (Schmid P, et al. NEJM. 2022). SG is a Trop-2–directed antibody-drug conjugate approved for pretreated metastatic TNBC (mTNBC). In Ph 3 ASCENT, SG significantly improved both progression-free survival and overall survival (OS) compared with standard chemotherapy (CT) in pts with mTNBC who received ≥2 lines of therapy, with a manageable safety profile (Bardia A, et al. NEJM. 2021). Preclinical data suggest that SG also potentiates the activity of ICIs. The ASCENT-05 study will assess the value of adding SG to a pembro-based adjuvant therapy in pts with RD after NAT. Methods: ASCENT-05/OptimICE-RD (AFT-65, NCT05633654) is an open-label, global, multicenter, randomized, phase 3 study that evaluates efficacy and safety of SG + pembro versus pembro ± cape (per treating physician discretion) in pts with TNBC and RD in the post-NAT setting. Key eligibility criteria include pts ≥18 years with a history of cT1, cN1-2 or cT2-4, cN0-2 TNBC with RD in the breast or lymph node(s) after NAT and surgery. TNBC diagnosis per local assessment is based on estrogen receptor and progesterone receptor < 10%, and HER2-negative per ASCO/CAP. Other inclusion criteria are receipt of ≥6 cycles of neoadjuvant anthracycline- and/or taxane-based CT ± PD-(L)1 inhibitor ± radiotherapy postoperatively as clinically indicated, and adequate organ function with ECOG performance status 0-1. Key exclusion criteria include metastatic disease, prior ipsilateral/contralateral invasive breast cancer, prior treatment directed to another stimulatory/coinhibitory T-cell receptor, HER2-directed agents or TOPO-1 inhibitors, evidence of recurrent or distant metastatic disease after preoperative therapy and surgery, germline BRCA mutations, myocardial infarctions ≤6 months of enrollment or history of serious ventricular arrythmia or LVEF < 50%, and active serious infections requiring treatment. Pts will be randomized 1:1 to receive SG (10 mg/kg IV on d1 and d8, every 21d for 8 cycles) + pembro (200 mg IV on d1 every 21d for 8 cycles). Cape (1000 mg/m
2
twice daily, orally on d1-14, every 21d for 8 cycles) may be added to pembro in the control arm. The primary endpoint is invasive disease-free survival. Key secondary endpoints include OS, distant disease-free survival, incidence of treatment-emergent adverse events and clinical laboratory abnormalities, and time to worsening of quality of life based on FACT-B TOI scores. ASCENT-05 will enroll ~1500 pts and is currently open for recruitment. Clinical trial information: NCT05633654 .
1061
Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor ...antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . Table: see text
1078
Background: The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) gene is mutated in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal ...growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, is indicated in combination with fulvestrant (FUL) for pts with HR+, HER2− ABC following progression on/after endocrine therapy (ET)-based treatments (tx). Primary analyses from the 3 cohorts of the Phase 2, open-label, noncomparative BYLieve study demonstrated the efficacy of ALP + ET in pts with HR+, HER2–, PIK3CA-mutated ABC who progressed on/after other tx, including immediately after a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Presented here are efficacy and safety data from the full 3 cohorts of the BYLieve study. Methods: Pts in all 3 cohorts completed ≥18 mo follow-up plus 1 mo safety follow-up. Efficacy assessments included DoR, BOR, PFS, PFS2, and OS. Safety/tolerability of ALP were also assessed. Median (m) PFS, PFS2, and OS were assessed by Kaplan-Meier methodology per local investigator assessment. Results: Cohort A (ALP + FUL) comprised 127 pts whose immediate prior tx was CDK4/6i + aromatase inhibitor (AI); Cohort B (ALP + letrozole) enrolled 126 pts whose immediate prior tx was CDK4/6i + FUL. In Cohort C (ALP + FUL), 126 pts had disease progression on/after AI and received CT or ET as immediate prior tx. Median follow-up for the 3 cohorts was 21.8, 25.3, and 18.5 mo, respectively. mPFS in Cohorts A, B, and C was 8.0 mo (95% CI, 5.6-8.6), 5.6 mo (3.7-7.1), and 5.6 mo (5.4-8.1), respectively; mPFS2 was 15.2 mo (95% CI, 11.4-21.7), 13.0 mo (10.2-13.9), and 13.5 mo (11.5-17.3), respectively. mOS in Cohorts A, B, and C was 27.3 mo (95% CI, 21.3-32.7), 29.0 mo (24.5-34.8), and 20.7 mo (16.9-28.1), respectively. Efficacy of ALP + ET in 2nd and 3rd lines will be presented. In Cohorts A, B, and C, respectively, 29 (22.8%), 19 (15.1%), and 23 (18.3%) pts discontinued tx due to adverse events (AEs). The most common any grade AEs in all 3 cohorts (A; B; C) were diarrhea (n = 82, 64.6%; n = 86, 68.3%; n = 68, 54.0%), hyperglycemia (n = 76, 59.8%; n = 82, 65.1%; n = 85, 67.5%), nausea (n = 59, 46.5%; n = 69, 54.8%; n = 51, 40.5%), rash (n = 40, 31.5%; n = 39, 31.0%; n = 51, 40.5%), and fatigue (n = 39, 30.7%; n = 39, 31.0%; n = 44, 34.9%). Hyperglycemia was the most common grade ≥3 AE, observed in 37 (29.1%), 32 (25.4%), and 30 (23.6%) pts in Cohorts A, B, and C, respectively. Conclusions: After ≥18 mo follow-up, with mature data, ALP + ET demonstrated clinical activity in BYLieve Cohorts A, B, and C. Within the trial, ALP + ET showed median OS between 20.7 mo and 29.0 mo following prior CDK4/6i, chemotherapy, or ET. AEs associated with ALP were well defined and manageable, with no new safety signals observed in any cohort. Clinical trial information: NCT03056755 .
1003
Background: Treatment of HR+/HER2– mBC includes sequential endocrine therapy (ET) combined with targeted agents followed by sequential single-agent chemotherapy (CT), which is associated with ...poor outcomes and quality of life. SG is a Trop-2–directed antibody-drug conjugate approved in multiple countries for pts with metastatic triple-negative breast cancer who received ≥1 prior systemic therapy and in the US for pts with pretreated HR+/HER2- mBC. In the phase 3 TROPiCS-02 study, SG demonstrated a statistically significant OS benefit versus treatment of physician’s choice (TPC) in pts with pretreated, ET-resistant HR+/HER2– mBC at the 2nd planned interim OS analysis with 390 events (median, 14.4 vs 11.2 mo; HR, 0.79 95% CI, 0.65-0.96; P=0.02; Rugo HS, et al. ESMO 2022. LBA76); this is considered the final analysis per the protocol. Here, we report the results of an exploratory analysis of OS from TROPiCS-02 with a longer median follow-up (12.75 mo). Methods: Eligible pts withHR+/HER2– mBC who received prior taxane, ET, CDK4/6 inhibitor, and 2-4 prior lines of CT were randomly assigned 1:1 to receive SG (10 mg/kg IV d1 and 8, every 21 d) or TPC until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints included OS and safety. In an exploratory analysis, we evaluated OS by HER2 immunohistochemistry (IHC). Results: In total, 543 pts (median prior CT for mBC, 3; visceral metastases, 95%) were randomized to receive SG (n=272) or TPC (n=271). At data cutoff (Dec 1, 2022), 437 OS events had occurred (median follow-up, 12.75 mo), with 47 (8.7%) new deaths in the SG versus TPC groups (22 8.1% vs 25 9.2%) since the 2nd planned interim analysis. With this extended follow-up, SG continues to demonstrate improved OS versus TPC (median, 14.5 vs 11.2 mo; HR, 0.79 95% CI, 0.65-0.95; nominal P=0.01). The OS rates (95% CI) for SG versus TPC were 60.9% (54.8-66.4) and 47.1% (41.0-53.0) at 12 months, 39.2% (33.4-45.0) and 31.7% (26.2-37.4) at 18 months, and 25.6% (20.4-31.1) and 21.1% (16.3-26.3) at 24 months. Overall, 92% of pts were evaluable for HER2 status by IHC (HER2 IHC0, n=217; HER2-low, n=283). SG demonstrated improved OS versus TPC in the HER2 IHC0 (median, 13.6 vs 10.8 mo; HR, 0.86 95% CI, 0.63-1.13) and HER2-low (median, 15.4 vs 11.5 mo, HR, 0.74 95% CI, 0.57-0.97) groups. Updated safety will be reported at the time of presentation. Conclusions: The final OS analysis of the TROPiCS-02 study confirms the clinically meaningful OS benefit of SG over single-agent CT in pts with pretreated, endocrine-resistant HR+/HER2–mBC. This improvement was independent of HER2-low status. This analysis reinforces SG as an effective and safe treatment for this pt population with limited treatment options. Clinical trial information: NCT03901339 .
Abstract only
TPS1100
Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase II trial ...in patients (pts) with heavily pretreated, metastatic HER2+ breast cancer (BC), T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic BC after ≥ 2 prior anti-HER2 based regimens. For HER2-low BC and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase I trial of T-DXd in pts with HER2-low BC or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase Ib study of T-DXd in combination with pembrolizumab in pts with locally advanced/metastatic HER2-expressing BC or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). Methods: This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) pts in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with BC (HER2+ IHC 3+ or IHC 2+/ISH+ with progression on prior T-DM1; and HER2-low IHC 1+ or IHC2+/ISH- with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing IHC ≥ 1+ or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 pts planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics. Clinical trial information: NCT04042701 .
