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PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

9058 Background: Datopotamab deruxtecan (Dato-DXd; DS-1062) is an ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Methods: TROPION-PanTumor01 (NCT03401385) is a multicenter dose-escalation/expansion study evaluating Dato-DXd administered Q3W in patients (pts) with advanced NSCLC (since expanded to other tumor types, excluded from this analysis). Efficacy and safety were evaluated in 175 pts for dose analysis. Pharmacometric analyses (population pharmacokinetics [popPK] and exposure-response modeling) were conducted across doses to inform dose selection for further development. Results: At data cutoff (Sept 4, 2020), median follow-up was 7.4 mo (range, 0.10-21.7 mo). Select all-grade TEAEs were 1.5- to 2-fold higher in the 8 mg/kg vs 4 and 6 mg/kg cohorts: vomiting (34% vs 12% and 18%), anemia (28% vs 4% and 16%), diarrhea (20% vs 6% and 11%), and mucositis (29% vs 6% and 13%). Rates of grade ≥3 drug-related TEAEs and serious drug-related TEAEs were ≥2-fold higher with the 8 mg/kg dose (n = 80; 34% and 20%) relative to the 4 mg/kg (n = 50; 10% and 8%) and 6 mg/kg (n = 45; 16% and 9%) doses. Rates of drug-related interstitial lung disease (ILD), as determined by an independent adjudication committee, were higher in the 8 mg/kg cohort (15% vs 2% and 2% in the 4 and 6 mg/kg cohorts); 3 pts in the 8 mg/kg cohort experienced grade 5 ILD. Dose interruptions and reductions due to TEAEs increased with dose (4 mg/kg: 4% and 2%; 6 mg/kg: 20% and 9%; 8 mg/kg: 20% and 31%). More pts in the 8 mg/kg cohort discontinued Tx early due to AEs (15%) compared with those in the 4 mg/kg (4%) and 6 mg/kg (7%) cohorts. ORRs determined by blinded independent central review were similar: 8 mg/kg, 25% (20/80); 6 mg/kg, 21% (8/39); and 4 mg/kg, 23% (9/40). Preliminary median PFS (95% CI) was 5.4 mo (4.1-7.1 mo) in the 8 mg/kg cohort, 8.2 mo (1.5-11.8 mo) in the 6 mg/kg cohort, and 4.3 mo (2.0 mo-NE) in the 4 mg/kg cohort. PFS was limited by early censoring due to immature duration of follow-up, with the majority of pts having ≤3 mo of follow-up in the 4 (66%) and 6 mg/kg (67%) cohorts vs 8 mg/kg (46%) cohort. In pharmacometric analyses, tumor-size change from baseline and probability of complete response/partial response positively correlated with exposure (AUC) of Dato-DXd. Incidences of dose reduction and grade ≥2 stomatitis/mucositis were also positively correlated with exposure; projected probabilities in a virtual population bootstrapped from pts with NSCLC in the popPK data confirmed these trends. Updated results will be presented. Conclusions: A Dato-DXd dose of 6 mg/kg was selected for the randomized, phase 3, TROPION-Lung01 trial (NCT04656652) based on better tolerance and improved efficacy, including a trend toward increased PFS. Clinical trial information: NCT03401385.

3505 Background: T-DXd is an antibody–drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data. Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH−; C: IHC1+). The primary end point was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary end points were disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/16 pts; 95% CI, 19.8-70.1) in pts with prior anti-HER2 therapy, 57.5% (23/40 pts; 95% CI, 40.9-73.0) in pts with IHC3+ status, and 7.7% (1/13 pts; 95% CI, 0.2-36.0) in pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5). Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in this pt population. The safety profile was consistent with prior results; ILD continues to be recognized as an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in pts with HER2-overexpressing mCRC. Clinical trial information: NCT03384940.

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

4048 Background: T-DXd is an antibody–drug conjugate comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. DESTINY-Gastric01 (DS8201-A-J202; ClinicalTrials.gov, NCT03329690) is an open-label, multicenter, randomized, phase 2 trial of T-DXd in patients with HER2-positive advanced gastric cancer (GC) or GEJ adenocarcinoma. In the primary analysis (101 OS events; median survival follow-up, 12.3 mo), T-DXd showed statistically significant benefit vs standard chemotherapy in objective response rate (ORR) and OS (Shitara K, et al. N Engl J Med. 2020;382:2419-2430); here, we present the final OS analysis as well as updated efficacy and safety. Methods: Patients (pts) with locally advanced or metastatic, centrally confirmed HER2-positive (IHC3+ or IHC2+/ISH+ on archival tissue) GC or GEJ cancer that had progressed after ≥2 previous lines of therapy including trastuzumab were randomly assigned 2:1 (T-DXd 6.4 mg/kg Q3W or physician’s choice [PC] irinotecan [I] or paclitaxel [P]). Pts were stratified by country, ECOG performance status (0, 1), and HER2 status. Primary end point was ORR by independent central review. Key secondary end points were OS, duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), confirmed ORR, and safety. Final OS analysis was performed at 133 OS events. Results: 187 pts received T-DXd (n = 125) or PC (n = 62 [55 I; 7 P]); 79.7% of pts were Japanese and 20.3% were Korean. Pts had a median of 2 prior lines of therapy, and 44.4% had ≥3. At data cutoff (June 3, 2020), 8% of T-DXd and 0% of PC pts remained on treatment (median survival follow-up, 18.5 mo). OS was improved with T-DXd vs PC (median OS, 12.5 vs 8.9 mo; hazard ratio [HR], 0.60 [95% CI, 0.42-0.86]); 12-month OS, 52.2% vs 29.7%. ORR was 51.3% (61/119; 11 CR; 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < 0.0001); confirmed ORR, 42.0% (50/119; 10 CR; 40 PR) vs 12.5% (7/56; all PR) ( P = 0.0001); DCR, 86.6% vs 62.5% ( P = 0.0003); confirmed median DOR, 12.5 vs 3.9 mo; median PFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = 0.0003). Grade ≥3 AEs occurred in 85.6% of T-DXd pts vs 56.5% with PC; the most common were neutrophil count decreased (49.6%, 22.6%), anemia (38.4%, 22.6%), and white blood cell count decreased (20.8%, 11.3%). 16 pts (12.8%) had T-DXd–related interstitial lung disease (ILD; 13 grade 1/2, 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. As reported in the primary analysis, there was 1 T-DXd–related death from pneumonia (non-ILD). Conclusions: With additional follow-up after the primary analysis, T-DXd continued to demonstrate OS benefit and clinically relevant improvement in ORR compared with standard chemotherapy, and a manageable safety profile, in HER2-positive advanced GC or GEJ adenocarcinoma. Clinical trial information: NCT03329690.

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .

4513 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or GEJ adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Methods: Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. Results: 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < .0001); confirmed ORR, 42.9% vs 12.5% ( P < .0001); DCR, 85.7% vs 62.5% ( P = .0005); mDOR, 11.3 vs 3.9 mo; mPFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). OS was significantly prolonged with T-DXd (mOS, 12.5 vs 8.4 mo; HR, 0.59 [95% CI, 0.39-0.88]; P = .0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were neutrophil count decreased (51.2%; 24.2%), anemia (37.6%; 22.6%), and white blood cell count decreased (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. Conclusions: T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma. Clinical trial information: NCT03329690 .

4000 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (DS8201-A-J203; NCT03384940) is a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC. Methods: Pts with centrally confirmed HER2-expressing, RAS–wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C. Results: At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y (range, 27-79 y), 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4 (range, 2-11); all pts had prior irinotecan. Median treatment duration was 3.5 mo (95% CI, 2.1-4.3 mo; cohort A, 4.8 mo [95% CI, 3.9-5.8 mo]); 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6%-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached (95% CI, 4.2 mo-NE). The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8%-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2%-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohorts B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of pts (48/78); the most common (≥10%) were decreased neutrophil count (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug-related deaths]). Conclusions: Overall, T-DXd 6.4 mg/kg q3w demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention. Clinical trial information: NCT03384940 .

9504 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase I trial, patients (pts) with HER2-mutated NSCLC who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, WCLC 2018). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase II study of T-DXd in pts with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2 mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). Methods: Pts were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety. Results: At data cutoff (25 Nov 2019), 42 pts (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had central nervous system metastases; ECOG performance status was 0 in 23.8% of pts and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most pts (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment; median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of pts remained on treatment. Confirmed ORR by ICR among the 42 pts was 61.9% (95% CI, 45.6%-76.4%); median DOR was not reached at data cutoff; 16 of 26 responders remained on treatment at data cutoff; DCR was 90.5% (95% CI, 77.4%-97.3%); estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo). All pts (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 pts (59.5%), dose reduction in 16 pts (38.1%), and treatment discontinuation in 10 pts (23.8%). Conclusions: T-DXd demonstrated promising clinical activity with high ORR and durable responses in pts with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies. Clinical trial information: NCT03505710 .

118 Background: DS-8201a is a HER2 targeting antibody-drug conjugate of high drug to antibody ratio (7 to 8) with a novel linker and topoisomerase I inhibitor. In preclinical studies, DS-8201a demonstrated a broad antitumor spectrum including efficacy against low HER2 expressing cancers. Interim results of the first-in-human phase 1 trial reported an overall confirmed response rate of 40.2% across several tumor types including breast and gastric (data cutoff of May 11, 2017). Here, we present updated results focusing on HER2 expressing gastric cancer (GC) subjects as of August 1, 2017. Methods: The trial consists of part 1, dose-escalation, and part 2, dose expansion cohorts. Part 2 included the cohort for subjects with HER2 expressing GC previously treated with trastuzumab. HER2 status was determined by IHC, and/or FISH according to ASCO CAP guidelines. Results: Seven GC subjects were enrolled in Part 1and 41 subjects were enrolled in Part 2. The median number of prior anticancer treatment was 3. In Part 1, confirmed ORR across doses was 43% (3/7). One out of two subjects with HER2 low (IHC2+/ISH-) showed PR. In Part 2, confirmed ORR and DCR were 44% (16/36) and 78% (28/36), respectively with 83% of subjects experiencing tumor shrinkage. Currently, the median DoR and PFS are ≥31 weeks and 25 weeks, respectively. For subjects enrolled in part2b, the most common AEs of any grades were nausea (All 71%; ≥Gr3 2%), decreased appetite (All 61%; ≥Gr3 10%), vomiting (All 22%; ≥Gr3 0%) and platelet count decreased (All 32%; ≥Gr3 17%). Five subjects (10%) discontinued drug treatment due to AE. Conclusions: DS-8201a demonstrated promising antitumor activity in heavily pretreated subjects with HER2 expressing GC. Clinical trial information: NCT02564900.

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]

548 Background: For gastro-intestinal cancers, irinotecan is used as first or second line, either as single agent or in combination therapy. The patient response rate is low and drug resistance mechanism is not understood. Irinotecan like other topoisomerase I inhibitors (camptothecin and their analogues, CPTs) are not MDR substrates, topoI mutations are rare and other potential mechanisms have not been validated. One of the most distinct cellular responses to CPT is the proteolytic degradation of topoI by the ubiquitin proteosomal pathways (UPP) and the rate of topoI degradation determines the drug response. Using a functional proteomic approach we have defined the mechanism of UPP mediated topoI degradation and have identified the molecular determinant of CPT resistance. We have demonstrated that higher basal level of topoI-pS10 drives rapid topoI ubiquitination and degradation in response to CPT. Methods: We have raised mouse monoclonal antibody that specifically binds with topoI-pS10 for immunohistochemistry (IHC) staining of the formalin fixed paraffin embedded (FFPE) slides. In our first cohort of retrospective study, 48 metastatic colorectal cancer tissues were immunostained with anti-topoI-pS10 and nuclear staining was quantitatively analyzed. Results: Data were summarized with descriptive statistics. ROC analysis was used to assess diagnostic characteristics across different thresholds. Mean and median positive nucleation values correlated strongly with drug response. Median nucleation level among non-responders was 69% compared to 9% for responders (Wilcoxon p = 0.0006). ROC analysis demonstrated an optimal threshold between 30-40% nucleation. Using a threshold of 35%, the estimated sensitivity was 82% (95% CI 56-95) and specificity was 77% (57-89). Estimated positive and negative predicted values were 67% (43-85) and 88% (69-97) respectively. We have also got similar results in 80 patient gastric cancer retrospective studies. Conclusions: Basal level of topoI-pS10 can be used as a predictive biomarker for topoI inhibitors. Our IHC based test can be adopted in clinical pathology settings to determine the topoI-pS10 level and stratify the patient population for CPT based therapy.

10052 Background: Sorafenib, an orally bioavailable, multi-target tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated single agent activity in various malignan...

550 Background: Etirinotecan pegol (EP; NKTR-102) is the first long-acting topoisomerase I inhibitor designed to concentrate and provide continuous tumor exposure. This study was designed to identify the recommended dose of EP in combination with 5-fluorouracil (5FU; 400/2400 mg/m2 by bolus, then 46-hour infusion) and leucovorin (LV; 400 mg/m2). Methods: Patients (pts) were enrolled in a standard 3+3 design. Initially, pts received all 3 agents every 2 weeks (schedule A). Due to higher SN38 exposure with the triplet compared to single-agent EP in the 25 mg/m2dose cohort, the schedule was modified to deliver all 3 agents for the first 4 doses at 2-week intervals; 5FU/LV continued at 2-week and EP at 4-week intervals thereafter (Schedule B). The protocol enrolled adults with an advanced malignancy; pts had ECOG 0 or 1 with adequate organ function. Results: 26 pts were enrolled in 5 cohorts: median age 63 (44-80); male:female 12:14; median prior regimens 3.5 (1-9). Schedule A: 25 mg/m2 (n=8, 6 evaluable for toxicity) and 50 mg/m2 (n=3). Schedule B: 50 mg/m2 (n=3), 75 mg/m2 (n=6) and 100 mg/m2 (n=6). DLTs: Grade (G) 3 abdominal pain following the infusion (1 pt; 25 mg/m2); G3 nausea/dehydration and G4 neutropenia (NTP) >3 days (2 pts; 100 mg/m2). 5 pts at a dose of 75 mg/m2 had a dose delay due to NTP or diarrhea in the first 2 months. Common G3+ toxicity at 75 mg/m2: NTP (50%), diarrhea and lymphopenia (both 33%). At >50 mg/m2EP, SN38 exposure was comparable to that previously observed after single-agent EP. 5-FU exposure: comparable to prior reports. Two pts (ovarian, gall bladder) had a PR; 11 additional pts had stable disease >6months (3 NSCL 6M-9M; 3 CRC 6-8M; esophageal 7M, desmoplastic round cell sarcoma and pheochromocytoma 6M) or tumor marker response (pancreatic pt who had received prior irinotecan 93%, 9M; breast 82%, 5M). ORR or SD>6M was observed in 8 of the 12 patients in the two highest dose levels. Conclusions: 75 mg/m2 EP with 5FU/LV (Schedule B) shows promising clinical activity with an acceptable safety profile. The combination warrants further clinical testing. Single-agent EP is currently being studied in a phase 3 trial in breast cancer compared to physician’s choice (n=852).

2534 Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m2. After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (>10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.

2598 Background: NKTR-102 demonstrates significant anti-tumor activity with a tolerable toxicity profile in pts with platinum-resistant/refractory ovarian or metastatic breast cancers. NKTR-102 is ...

e13570 Background: Namitecan (N) is a topoisomerase I inhibitor with superior antitumor activity (especially in squamous cell ca., SCC) and a more favourable safety profile than irinotecan and topo...

5098 Background: This study is to evaluate the efficacy and toxicity of belotecan (CKD-602), a new camptothecin analogue topoisomerase I inhibitor, combined with platinum as the second-line chemoth...

2073 Background: The novel oral lipophilic camptotecan gimatecan (ST1481; NVP-LBQ707) has shown antitumor activity against malignant glioma xenografts and synergistic effects with temozolomide (Vas...

14618 Background: Lapatinib is a HER1 and 2 tyrosine kinase inhibitor (TKI). Little is know about its interaction with other chemotherpy drugs. In this work investigate interactions between lapatin...

2512 Background: Gimatecan (Gim), a novel oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than irinotecan and t...

10565 Background: DNA double-strand breaks (DSBs) caused by exposure to DNA damaging agents initiate phosphorylation of histone H2AX to form gamma-H2AX, which is considered a surrogate marker of DSBs. However, it is a challenge to quantitatively measure gamma-H2AX in clinical samples such as tumor biopsies. The aim of this study was to develop an immunohistochemical detection method for gamma-H2AX and to quantitatively evaluate the levels of gamma-H2AX in paraffin-embedded tumor samples. Methods: Human breast cancer MCF-7 cells were treated with the topoisomerase I inhibitor irinotecan at 1 μM or vehicle for 1 h, and fixed in 10% neutral buffered formalin and embedded in paraffin. Staining with gamma-H2AX antibody was performed on sections of treated MCF-7 cells, tumor specimens, and biopsies at baseline and after doxorubicin-containing chemotherapy from cancer patients. Numbers of foci and level of gamma-H2AX expression per tumor nucleus were determined by manual counting under a light microscope and an Automated Cellular Imaging System. Results: There was a rise in the mean numbers of nuclear foci and intensity of gamma-H2AX in MCF-7 cells treated with irinotecan versus vehicle (19.9 ± 2.7 vs. 9.95 ± 3.6; P < 0.0001 and 61.2 ± 8.5 vs. 16.2 ± 13.6; P < 0.0001 by Wilcoxon rank sum test). The level of gamma-H2AX foci in human tumor samples was 18.8 ± 13.1, 44.8 ± 14.5, 51.2 ± 20.8, or 69.7 ± 21.2 in carcinomas of the breast, colon, ovary, or prostate. In a patient with stable disease, levels of gamma-H2AX foci were 62.7 ± 26.9 at baseline and 67.2 ± 25.3 after doxorubicin-containing regimen chemotherapy. Conclusions: Our data suggest that the quantitative immunohistochemical detection of gamma-H2AX levels is facilitated by a digital imaging system, and is a reliable method to measure the effects of DNA damaging agents in cells and paraffin-embedded human tumor samples. Its application may help evaluate tumor response to various DNA damaging agents currently in the clinic and those presently undergoing clinical development. No significant financial relationships to disclose.

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]

2013 Background: S-CKD602 is a pegylated STEALTH liposomal formulation of CKD-602, a semi-synthetic analogue of camptothecin (CPT) and topoisomerase I inhibitor. Preclinical studies have shown that prolonged exposure to CPT achieves the greatest antitumor activity. STEALTH liposomes prolong the circulation time in plasma, achieve high and extended drug exposure in tumor, and provide a convenient dosing schedule. Methods: Patients (pts) were administered S-CKD602 IV over 1 h once every 3 wks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels ranged from 0.1–2.5 mg/m2. Serial plasma samples were obtained prior to administration to 96 h after administration, and on days 8 and 15 of cycle 1. Plasma samples were processed to measure concentrations of encapsulated (E), released (R), and sum total (E+R) CKD602 total (lactone + hydroxyl acid) by LC-MS/MS. Area under the plasma conc versus time curve (AUC0-∞) and t1/2 were estimated. Results: 45 pts (21 male) have been treated: median age 62 y (range: 33–79 y); ECOG status: 0 and 1 (43 pts), 2 (2 pts). The majority of reported adverse events were grade (G) 1 and 2. Frequent nonhematological toxicities were asthenia, nausea, diarrhea, vomiting, and anorexia. Dose-limiting toxicities of G3 mucositis occurred in 1/6 pts at 0.3 mg/m2, G3/4 bone marrow suppression in 2/3 pts at 2.5 mg/m2, and G3 febrile neutropenia in 1/6 pts at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Stable disease for ≥ 6 cycles occurred in 5 pts (hepatocellular carcinoma (CA), thyroid, prostate, 2 pts sarcoma). Partial responses occurred in 2 pts with ovarian CA (1.7 and 2.1 mg/m2). At 2.1 mg/m2, the mean ± SD AUC and t1/2 of sum total S-CKD602 were 44 ± 33 μg/mL·h and 18 ± 8 h, respectively. In all plasma samples, >90% of drug was encapsulated. Conclusions: S-CKD602 represents a promising new STEALTH liposomal CPT agent with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 IV once every 3 wks are planned. Prolonged plasma exposure over 1 to 2 wks is consistent with STEALTH liposomes and provides extended exposure compared with non-liposomal CPT. (Supported by ALZA and NIH/NCCR/GCRC #5M01 RR 00056). [Table: see text]

2015 Background: CT-2106, a camptothecin (CPT) conjugate, is a topoisomerase I inhibitor. Covalent binding through the hydroxyl group of CPT to polyglutamate, a biodegradable polymer of glutamic acid, enhances CPT aqueous solubility and prevents opening of the lactone ring and subsequent CPT binding to albumin. Responses were observed in a Q3 week dosing study in which the maximum tolerated dose (MTD) was 75 mg/m2. Objectives of this study are to determine the MTD and pharmacokinetics (PK) of CT-2106 given weekly to pts with advanced cancer. Methods: Pts received CT-2106 (10 min IV infusion) on days 1, 8, and 15 of each 28 day cycle. Toxicity (NCI CTC v3) and tumor response (RECIST) were assessed. Plasma was analyzed for conjugated and unconjugated CPT by liquid chromatography and tandem mass spectrometry. Results: Enrollment is complete with 21 evualuable pts. Dose limiting toxicities (DLT) are shown in the table . Median age = 60 years (range 36–83), median doses = 6 (1–9), median prior therapies = 3 (1–6). Most pts (12) had melanoma. In a Q3 week study assessments of conjugated and unconjugated CPT demonstrated that CT-2106 provides prolonged exposure to conjugated CPT and slow, progressive release of active CPT from the polymeric backbone. The PK of unconjugated CPT is dependent on the disposition profile of conjugated CPT; unconjugated CPT elimination is formation rate limited. The distribution of conjugated CPT appears to be restricted to extracellular body fluids. Total clearance includes renal excretion documented by substantial urinary excretion levels and CPT cleavage via metabolic pathways. Accumulation of conjugated or unconjugated CPT was not observed with repeated Q3 week dosing. PK in this weekly dosing study will be presented. Conclusions: CT-2106 is generally well tolerated without the toxicities normally associated with CPT, specifically hemorrhagic cystitis and severe diarrhea. The MTD is 25–35 mg/m2 in these heavily pretreated pts. [Table: see text] [Table: see text]

5088 Background: Gimatecan, a new camptothecin derivative, is a potent topoisomerase I inhibitor, active by oral route. Methods: A multicenter two stage Simon design phase II study was performed to evaluate the single agent antitumor activity of gimatecan. Secondary objectives were safety, time to event/time related parameters, and translational medicine evaluations. Women with advanced epithelial ovarian, fallopian tube or peritoneal cancer who had progressed or recurred after prior treatment with platinum and taxanes, had a progression-free interval from last platinum-based therapy < 12 months, had measurable disease by RECIST or assessable by CA 125 (GCIG criteria) and a ECOG performance status ≤ 1 were eligible. Gimatecan 0.8 mg/m2 was administrated orally for five consecutive days every four weeks. Radiological response was assessed every two cycles. Results: From June to December 2005, 70 women [median age 61 years (range 37–79)] were treated in 10 European sites. Number of prior chemotherapy regimens was: 1 in 20, 2 in 35, 3 in 15 patients, respectively. Progression-free interval from last platinum-based therapy was 0–6 months in 51 patients and 6–12 months in 19 patients. The study is still ongoing, and to date 40 consecutive patients are assessable. Preliminary response analysis indicated a 23.5% response rate based on CA 125 (8/34) and a 10% response rate based on RECIST (3/29). Main toxicity was hematological, namely thrombocytopenia and neutropenia. Conclusions: Preliminary results suggest that oral gimatecan administered as single agent is active, with bone marrow suppression resulting at present as the main toxicity in these patients previously treated with platinum and taxanes. However, many patients are still on treatment and data need to mature to have a broader picture of activity and safety. [Table: see text]

2070 Background: CPT-11 (topoisomerase I inhibitor) and AMR (topoisomerase II inhibitor) are active against several solid tumors including NSCLC. Based on the preclinical data, this phase I trial w...

3560 Background: Irinotecan(CPT-11), a topoisomerase I inhibitor, is approved in the use of both first and second line chemotherapy in metastatic colorectal cancer (CRC) patients. Currently, no rel...

5172 Background: There is no standard chemotherapy regimen for R-OC and ER-OC. CPT-11 (a DNA topoisomerase I inhibitor) is active against OC. A combination of CPT-11 and DXR (a topoisomerase II inh...

3127 Background: CT-2106, a camptothecin (CPT) conjugate, is a new generation of topoisomerase I inhibitors designed to deliver higher, more effective chemotherapy to tumor tissue with less toxicit...

3587 Background: The topoisomerase I inhibitor, irinotecan (CPT-11), is widely available for pts with progressive disease despite first-line therapy with 5-fluorouracil (5-FU). Potential adverse to...

2114 Purpose: 5-Fluorouracil (5-FU) has been shown to modulate DNA repair activity. This study tests (1) what is the maximum tolerated dose of capecitabine (C) given for 10 days prior to cisplatin (P) and irinotecan (I); (2) the changes in DNA repair induced by C. Patients and Methods: Patients (pt) with incurable cancers were eligible if they had normal hematologic, renal and liver functions, and had not failed 5-FU analogs or topoisomerase I inhibitors. The first cycle was P+I day 1 and I day 8 and 15, 50 mg/m2 each, to serve as control. C was started at the second cycle at a dose of 500 mg/m2/day x 10 days for the first cohort prior to P+I, which was administered on day 11, 18, and 25. Increments were by 250 mg/m2/cohort. A 3+3 design was used. Blood was drawn for DNA repair studies before the first 3 cycles and before cisplatin for the first 2 cycles. DNA repair analyses will be performed by measuring the residual cisplatin concentrations in DNAs collected from these patients. Patients stayed on study...

7344 Background: Docetaxel has activity against a wide range of tumors and topotecan is a topoisomerase I inhibitor with activity in ovarian and small cell lung cancer. Docetaxel potentiates the cy...