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Lessons Learned Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors. Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules. Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors. Background Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors. Methods This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01–10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks. Results Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4–7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response. Conclusion Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.

Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.

TPS290 Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA30) and 50% (PSA50). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .

BackgroundMonoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously.MethodsThis open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival.ResultsOne hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0–52.8), and the disease control rate was 66.0% (95% CI 56.0–75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5–97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7–82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1–2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events.ConclusionsThis is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer.Trial registrationClinicalTrials.gov, NCT03667170. Registered 10 September 2018—Retrospectively registered,https://clinicaltrials.gov/ct2/show/NCT03667170.

TPS5106 Background: Bavdegalutamide (ARV-110) is a novel, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that targets wild-type androgen receptor (AR) and clinically relevant mutants. Bavdegalutamide demonstrated tumor growth inhibition in multiple xenograft models (eg, AR gene amplification, AR mutation, enzalutamide resistance, and enzalutamide insensitivity). In a phase 1/2 study (NCT03888612), bavdegalutamide showed clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received 1–2 prior novel hormonal agents (eg, abiraterone and/or enzalutamide), including heavily pretreated patients. Abiraterone is approved, in combination with a corticosteroid, to treat patients with mCRPC or with high-risk castration-sensitive prostate cancer (CSPC). Up to a third of patients treated with abiraterone develop primary resistance to this drug and nearly all patients experience disease progression. Here we describe a phase 1b study that will evaluate the combination of bavdegalutamide with abiraterone at the initiation of progression on abiraterone (prostate-specific antigen [PSA] progression without radiographic progression) to test if the addition of bavdegalutamide will overcome resistance to abiraterone and re-establish the AR pathway blockade in patients with prostate cancer. Methods: Eligible patients are men ≥18 years of age with histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients must be receiving ongoing treatment with stable doses of abiraterone and a concomitant corticosteroid for mCRPC or CSPC and have PSA progression ≥16 weeks after initiation of abiraterone, ≥2 rising PSA values measured ≥1 week apart, and no radiographic evidence of disease progression while receiving abiraterone. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analogue or inhibitor or orchiectomy is required. Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental AR-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities). Clinical trial information: NCT05177042.

TPS1120 Background: ARV-471 is a novel, potent, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets the ER. In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. In the phase 1 dose escalation portion (Part A) of the first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed antitumor activity in patients with ER+/HER2- locally advanced or metastatic breast cancer who had previously received endocrine therapy and a cyclin-dependent kinase (CDK)4/6 inhibitor; the clinical benefit rate (rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26%–56%) in 47 evaluable patients. The phase 2 VERITAC expansion cohort (Part B) is further evaluating ARV-471 monotherapy in this patient population. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant is a standard treatment option for patients with ER+/HER2- breast cancer who have had disease progression on endocrine therapy. ARV-471 plus palbociclib resulted in substantially greater tumor growth inhibition in xenograft models compared with palbociclib plus fulvestrant, supporting further investigation of the ARV-471 plus palbociclib combination in patients with ER+ breast cancer. Here we describe Part C of the phase 1/2 study, which evaluates the safety and clinical activity of ARV-471 plus palbociclib in patients with breast cancer who previously received endocrine therapy. Methods: Eligible patients (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- advanced breast cancer and have received ≥1 prior endocrine therapy and ≤2 prior chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor therapy is permitted. Patients with known symptomatic brain metastases requiring steroids are excluded. ARV-471 and palbociclib will be administered orally once daily in 28-day cycles; ARV-471 will be given continuously and palbociclib for 21 days followed by 7 days off treatment. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters. Clinical trial information: NCT04072952.

Non-small cell lung cancer (NSCLC) cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of abundant oxygen. Inhibition of aerobic glycolysis remains challenging when identifying potential cancer-specific inhibitors while maintaining or even boosting the anti-cancer immunity. Artemisinin derivatives DHA and AS have shown excellent anti-tumor and immunoenhancing roles in numerous malignancies, but the molecular mechanism of DHA and AS in regulating cancer glucose metabolism is largely unknown. In this study, we proved that DHA and AS inhibit NSCLC growth via prohibiting cancer cell aerobic glycolysis through ERK/c-Myc pathway. First, we proved that DHA and AS have comparable anti-cancer growth roles in both NSCLC cell lines and mouse Lewis Lung Cancer model. Then, our data clearly showed that DHA and AS dose- and time-dependently reduce the uptake of glucose, the production of ATP, and the secretion of lactate, the expression of glucose transporter GLUT1 and two key glycolysis-related enzymes hexokinase and lactate dehydrogenase, as well as the level of c-Myc. Finally, we generated c-Myc

17 Background: ARV-110 is a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets AR. Patients (pts) with mCRPC have limited treatment (tx) options due to decreasing AR dependence of tumors upon successive therapies. Previous phase 1 data indicated clinical activity for ARV-110 in heavily pretreated pts with mCRPC and suggested enhanced activity in pts with specific molecular profiles, eg, AR T878 and H875 mutations, leading to a phase 2 expansion (ARDENT) to further characterize ARV-110 in biomarker-defined pt subgroups. We report results of the ongoing phase 1/2 study. Methods: In phase 1, pts with mCRPC and disease progression after ≥2 prior therapies (enzalutamide and/or abiraterone required) received ARV-110 orally once or twice daily (QD or BID) in sequential cohorts (3 + 3 dose escalation design). Primary objectives were to assess ARV-110 safety and select the recommended phase 2 dose (RP2D). Phase 2 pts with mCRPC and 1–2 prior novel hormonal agents (NHAs) ± chemotherapy were assigned to 3 biomarker-defined subgroups: 1) AR T878 and/or H875 mutations, 2) AR L702H mutation or AR-V7 (variants not degraded by ARV-110 in nonclinical studies), and 3) wild-type AR or other AR alterations. A fourth subgroup enrolled pts based on clinical history of less prior tx: ≤1 therapy for mCRPC, 1 NHA, and no chemotherapy. Primary objective is to assess ARV-110 antitumor activity. Results: As of Aug 26, 2021, 173 pts were enrolled (67 in phase 1; 106 in phase 2). In phase 1, ARV-110 doses ranged from 35–700 mg QD or 210–420 mg BID; 420 mg QD was selected as the RP2D based on safety, pharmacokinetics, and efficacy. Across 140 biomarker-evaluable phase 1/2 pts with ≥1 month of prostate-specific antigen (PSA) follow-up, 26 with AR T878A/S and/or H875Y mutations had best PSA declines ≥50% (PSA50) and ≥30% (PSA30) of 46% and 58%, respectively, vs 10% and 23% in 114 pts without these mutations. Of 7 RECIST-evaluable pts with AR T878A/S and/or H875Y mutations, 6 had tumor shrinkage (2 with confirmed partial responses), and 4 remain on tx. Five of 19 (26%) PSA-evaluable pts in the fourth subgroup (only 1 prior NHA; no prior chemotherapy) achieved PSA50. Overall PSA50 and PSA30 response rates were 16% and 29%, respectively. There were no grade ≥4 tx-related adverse events (TRAEs) in 113 pts treated at the RP2D. The most common any grade TRAEs at the RP2D were nausea (42%; grade 3: 1%), fatigue (27%; grade 3: 1%), vomiting (23%; grade 3: 1%), decreased appetite (19%; grade 3: 0), diarrhea (15%; grade 3: 2%), and alopecia (11%). Conclusions: ARV-110, a novel AR protein degrader, demonstrates clinical activity in a post-NHA, heavily pretreated mCRPC pt population, with greatest PSA50 activity and RECIST responses in pts with AR T878 and/or H875 mutations, likely representing a particularly ARV-110–sensitive population. ARV-110 merits further investigation in pts with mCRPC. Clinical trial information: NCT0388861.

e16585 Background: Envafolimab is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneously (SC) injection. This study examined the feasibility of combining envafolimab with chemotherapy in advanced G/GEJ cancer. Methods: This study was a single arm, phase Ⅱ trial in adult subjects with previously untreated advanced G/GEJ cancer. Subjects received 8 cycles (2 weeks each) of envafolimab plus FOLFOX regimen followed by envafolimab and 5-FU until progression or unacceptable toxicity. Envafolimab was administrated SC at 5 mg/kg on day 1 of each cycle; FOLFOX consisted of 80 mg/m2 oxaliplatin, 400 mg/m2 5-FU and 400 mg/m2 leucovorin intravenous infusion on day 1, 2400 mg/m2 5-FU administered with a 48-hour continuous infusion on day 1 and 2. Tumor was assessed every 6 weeks per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Primary endpoints were safety and tolerability. Toxicity was graded using CTCAE v5.0. Secondary endpoints included objective response rate (ORR), duration of response (DoR). and progression free survival (PFS). Results: A total of 15 subjects were treated and evaluable for response. ECOG performance status was 1 in 80% of subjects. Majority had gastric cancer (86.7%). At the data cutoff, the minimum follow-up was 6 months. The treatment emergent adverse event (TEAE) occurrence was 100% (all grades) and 73.3% (grades 3-4). The most frequent grade 3-4 TEAE included neutrophil count decreased 46.7%, anemia 20.0%, and platelet disorder 20% (3/15). Confirmed ORR was 60% (unconfirmed ORR: 73.3%). Median DOR was not reached. Median PFS was 6.8 months. Conclusions: Envafolimab plus FOLFOX demonstrated a manageable safety profile with promising clinical efficacy as a first line therapy for advanced G/GEJ cancer. Clinical trial information: CTR20181124 .

3021 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc formulated for subcutaneous injection. This open-label phase II study evaluated the safety and antitumor activity of KN035 in patients with advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cancer. Methods: The study included patients aged ≥18 years with previously treated MSI-H/dMMR colorectal cancer (CRC) or other advanced solid tumors. MSI-H/dMMR status was assessed centrally for CRC and gastric cancer (GC) and locally for other tumors. KN035 was administered at 150 mg once weekly until progression, unacceptable toxicity, or withdrawal. Tumor assessments were every 8 weeks. The primary endpoint was the objective response rate per RECIST v1.1 by independent radiology review. The primary efficacy population (PEP) included patients with CRC who failed fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I) plus those with advanced GC who had failed at least one prior systemic treatment. This was a planned interim analysis performed after the first 50 patients in the PEP had at least two on-study tumor assessments (PEPi). Results: As of December 17, 2019, 103 patients with MSI-H/dMMR advanced cancers were enrolled at 25 centers in China. The PEPi included 39 patients with CRC and 11 with GC, with a median follow-up of 7.5 months. The overall population included 65 patients with CRC (24 had prior therapy with F and O or I), 18 with GC, and 20 with other tumors, with a median follow-up of 6.7 months. The confirmed objective response rate was 30% (95% CI: 17.9%, 44.6%) in the PEPi, 54.2% (95% CI: 32.8%, 74.4%) in the CRC patients who had prior therapy with F and O or I, and 34.0% (95% CI: 24.9%, 44.0%) in the overall population. Of patients who had an objective response at the interim analysis, 80% of those in the PEPi, 84.6% of CRC patients who had prior therapy with F and O or I, and 85.7% of those in the overall population were still responding at the time of data cutoff. Median progression-free survival was 6.6 months in both the PEPi and the overall population. Median overall survival was not reached in either population. Fourteen (13.6%) patients had grade 3–4 treatment-related adverse events. No grade 5 treatment-related adverse events, pneumonitis, or colitis were reported. Local injection-site reactions, all grade 1 or 2, were reported in nine patients. Conclusions: Envafolimab demonstrated durable anti-tumor activity with a manageable safety profile in patients with previously treated advanced MSI-H/dMMR cancer. Clinical trial information: NCT03667170 .

2609 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.

2608 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, formulated for subcutaneous (SC) injection. Methods: The escalation phase followed a modified 3+3 design with a 28-day DLT evaluation period and 8 dose levels were planned at 0.1, 0.3, 1.0, 2.5, 5 and 10 mg/kg SC weekly. One patient each was enrolled at 0.1 and 0.3 mg/kg dose levels. Additional dose levels followed traditional 3+3 design. Response was assessed per RECIST 1.1 every 12 weeks. Results: As of 11/2/2018, 17 patients were enrolled in the escalation phase (urothelial carcinoma (n=2), hepatic cell carcinoma (n=2), intrahepatic cholangiocarcinoma (n=2), thymic carcinoma (n=2), colorectal cancer£¨n=2£©£¬renal cell carcinoma (RCC, n=3), Squamous-cell lung carcinoma (n=1) and ovarian cancer (n=1)). The majority of subjects had advanced disease stage, stage IV (15/17) and stage III (2/17). A total of 7 subjects received radiotherapy, 16 subjects received surgery, and 13 subjects received systematic anti-cancer therapies from previous treatment. None had received prior checkpoint inhibitor treatment. Planned maximum dose of 10 mg/kg was reached (n=3) without DLT occurred. There was only one Grade 3 drug related Treatment Emergent Adverse Event (TEAE) occurred at 0.3 mg/kg dose level, which was immune related dermatitis and resolved later. All other drug related TEAEs were either Grade 1 or 2, with the most common events as elevated ALT (5/17) and elevated AST (4/17). Among all enrolled subjects, three subjects had confirmed PR, including one RCC subject at 2.5 mg/kg and one Intrahepatic cholangiocarcinoma subject at 5 mg/kg, and one cholangiocarcinoma subject at 10 mg/kg. Conclusions: KN035 exhibits a favorable safety profile and promising preliminary anti-tumor activity in patients with advanced malignancies. Clinical trial information: NCT03101488.

Background Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC). Design Patients (n = 130) with chemotherapy-naive ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety. Results Phased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64; P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively. Conclusion These results suggest further investigation of ipilimumab in ED-SCLC.

Purpose Ipilimumab, which is an anti–cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin. Patients and Methods Patients (N = 204) with chemotherapy-naive non–small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m2) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety. Results The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity. Conclusion Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.

Introduction: Nivolumab monotherapy has already shown efficacy and safety in the open-label, single-arm, phase II CheckMate 275 trial (objective response rate [ORR], 19.6%). Here, we report updated results with a minimum follow-up of 21.3 months together with additional exploratory biomarker analyses. Methods: Patients received nivolumab 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed ORR by blinded independent review committee (per Response Evaluation Criteria in Solid Tumors v.1.1). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). ORR was further examined by the duration of response (DoR) and time to response. Outcomes were evaluated in all patients and by tumor cell programmed death-1 ligand 1 (PD-L1) expression (cutoff ≥1% by Dako immunohistochemical staining). Myeloid-derived suppressor cells (MDSCs), defined as Lin− CD14+ HLA-DR-low/negative monocytic myeloid cells, were measured by flow cytometry in the circulation at baseline, and archival pretreatment biopsies were assessed for interferon gamma (IFN-γ) gene expression signature to assess associations with OS. Results: There were 270 treated patients. Median follow-up was 24.5 months. ORR was 20.4% for all treated patients. There were nine additional complete responses (CRs) since results with median follow-up of 11.5 months were reported (17; 6.3%). Of the 55 responders, 72.7% had DoR ≥6 months, 54.5% had DoR ≥12 months, and 30.9% had an ongoing response. Median (95% confidence interval [CI]) DoR for all treated patients was 17.7 (11.5-22.0) months. Median (95% CI) PFS and OS were 1.9 (1.9-2.3) and 8.6 (6.1-11.3) months, respectively. OS benefit was observed across tumor PD-L1 expression levels. The 1-year and 2-year OS rates (95% CI) were 40.3% (34.4-46.2) and 29.4% (23.9-35.1), respectively. The most common any-grade treatment-related adverse events were fatigue (18.1%), diarrhea (12.2%), pruritus (11.5%), and decreased appetite (9.3%). Lower vs higher baseline MDSCs were associated with longer OS in all patients and independent of tumor PD-L1 expression ( Conclusions: In this updated analysis of CheckMate 275, durable efficacy was observed with additional CRs since the previous report. No new safety signals were observed. A combination of immune-associated tumor and circulating biomarkers (as defined in this study) may identify patients with particularly favorable outcomes with nivolumab. Citation Format: Padmanee Sharma, Ari Baron, Andrea Necchi, Elizabeth R. Plimack, Sumanta K. Pal, Jens Bedke, Jose A. Arranz, Daniel Vaena, Marc-Oliver Grimm, Sergio Bracarda, Margitta Retz, Arlene Siefker-Radtke, Chikara Ohyama, Gary Grossfeld, Haolan Lu, Abdel Saci, Hao Tang, Matthew D. Galsky. Nivolumab monotherapy in patients with advanced platinum-resistant urothelial carcinoma: Efficacy and safety update and association between biomarkers and overall survival in CheckMate 275 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT178.

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Recently, public health professionals and other geostatistical researchers have shown increasing interest in boundary analysis, the detection or testing of zones or boundaries that reveal sharp changes in the values of spatially oriented variables. For areal data (i.e., data which consist only of sums or averages over geopolitical regions), Lu and Carlin (Geogr Anal 37: 265–285, 2005) suggested a fully model-based framework for areal wombling using Bayesian hierarchical models with posterior summaries computed using Markov chain Monte Carlo (MCMC) methods, and showed the approach to have advantages over existing non-stochastic alternatives. In this paper, we develop Bayesian areal boundary analysis methods that estimate the spatial neighborhood structure using the value of the process in each region and other variables that indicate how similar two regions are. Boundaries may then be determined by the posterior distribution of either this estimated neighborhood structure or the regional mean response differences themselves. Our methods do require several assumptions (including an appropriate prior distribution, a normal spatial random effect distribution, and a Bernoulli distribution for a set of spatial weights), but also deliver more in terms of full posterior inference for the boundary segments (e.g., direct probability statements regarding the probability that a particular border segment is part of the boundary). We illustrate three different remedies for the computing difficulties encountered in implementing our method. We use simulation to compare among existing purely algorithmic approaches, the Lu and Carlin (2005) method, and our new adjacency modeling methods. We also illustrate more practical modeling issues (e.g., covariate selection) in the context of a breast cancer late detection data set collected at the county level in the state of Minnesota.

Measuring a statistical model's complexity is important for model criticism and comparison. However, it is unclear how to do this for hierarchical models due to uncertainty about how to count the random effects. The authors develop a complexity measure for generalized linear hierarchical models based on linear model theory. They demonstrate the new measure for binomial and Poisson observables modeled using various hierarchical structures, including a longitudinal model and an areal-data model having both spatial clustering and pure heterogeneity random effects. They compare their new measure to a Bayesian index of model complexity, the effective number pD of parameters (Spiegelhalter, Best, Carlin & van der Linde 2002); the comparisons are made in the binomial and Poisson cases via simulation and two real data examples. The two measures are usually close, but differ markedly in some instances where pD is arguably inappropriate. Finally, the authors show how the new measure can be used to approach the difficult task of specifying prior distributions for variance components, and in the process cast further doubt on the commonly-used vague inverse gamma prior. Une mesure de la complexite des modeles lineaires generalises hierarchiques Il importe de mesurer la complexite des modeles statistiques a des fins comparatives et critiques. Dans le cas des modeles hierarchiques, cette tâche est toutefois compliquee par une certaine ambiguite concernant le denombrement des effets aleatoires. Les auteurs s'inspirent de la theorie des modeles lineaires pour elaborer une mesure de complexite adaptee aux modeles lineaires generalises hierarchiques. Ils en illustrent l'interet dans le cas ou des donnees binomiales ou de Poisson sont modelisees a l'aide de diverses structures hierarchiques, y compris un modele longitudinal et un modele pour donnees geospatiales incluant une tendance au regroupement spatial et une heterogeneite pure sous forme d'effets aleatoires. Les auteurs comparent leur nouvelle mesure a un indice bayesien de la complexite d'un modele, a savoir le nombre effectif pd de parametres (Spiegelhalter, Best, Carlin & van der Linde 2002); les comparaisons sont faites dans les cas binomial et de Poisson sur la base de simulations et de deux cas concrets d'application. Les deux mesures sont generalement liees mais different substantiellement dans certaines circonstances ou l'indice pD parait inapproprie. Enfin, les auteurs montrent quel nouvel eclairage leur mesure apporte a l'epineux probleme du choix de lois a priori pour les composantes de la variance, ce qui les conduit a jeter un doute de plus sur l'emploi pourtant repandu de la loi vague de type gamma inverse dans ce contexte.

In the analysis of spatially referenced data, interest often focuses not on prediction of the spatially indexed variable itself, but on boundary analysis, that is, the determination of boundaries on the map that separate areas of higher and lower values. Existing boundary analysis methods are sometimes generically referred to as wombling, after a foundational article by Womble (1951). When data are available at point level (e.g., exact latitude and longitude of disease cases), such boundaries are most naturally obtained by locating the points of steepest ascent or descent on the fitted spatial surface (Banerjee, Gelfand, and Sirmans 2003). In this article, we propose related methods for areal data (i.e., data which consist only of sums or averages over geopolitical regions). Such methods are valuable in determining boundaries for data sets that, perhaps due to confidentiality concerns, are available only in ecological (aggregated) format, or are only collected this way (e.g., delivery of health-care or cost information). After a brief review of existing algorithmic techniques (including that implemented in the commercial software BoundarySeer), we propose a fully model-based framework for areal wombling, using Bayesian hierarchical models with posterior summaries computed using Markov chain Monte Carlo methods. We explore the suitability of various existing hierarchical and spatial software packages (notably S-plus and WinBUGS) to the task, and show the approach's superiority over existing nonstochastic alternatives, both in terms of utility and average mean square error behavior. We also illustrate our methods (as well as the solution of advanced modeling issues such as simultaneous inference) using colorectal cancer late detection data collected at the county level in the state of Minnesota.

Breast tumors that lack estrogen responsiveness have a poor prognosis. Despite the critical importance to breast cancer treatment, little is known about the loss of estrogen responsiveness and the development of antiestrogen resistance. We have examined the regulation of estrogen-induced proliferation, estrogen regulation of progesterone receptor (PR) expression, and estrogen signaling pathways in estrogen receptor (ER) positive (MCF-7 and T47D) breast cancer cell lines by specific extracellular matrix proteins (ECM) under serum-free conditions. Estrogen, supplemented with submaximal concentrations of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF), stimulated DNA synthesis of MCF-7 cells 7- to 10-fold and T47D cells 2-fold on collagen I or fibronectin. However, estrogen-induced proliferation was greatly reduced on laminin. In contrast, IGF-I or EGF, alone, stimulated proliferation of MCF-7 and T47D cells on all ECM. Thus, ER1 breast cancer cells were not refractory to mitogens when cultured on laminin. Similarly, estrogen induction of PR occurred on fibronectin or collagen I, but not on laminin. While ER content was similar on all ECM, estrogen stimulation of estrogen response element (ERE)-luciferase activity was significantly lower in MCF-7 cells cultured on laminin. Therefore, changes in ECM composition that occur in breast cancer may alter estrogen-responsiveness and the effectiveness of antiestrogen therapies in ER1 breast cancer cells. (Endocrinology 141: 2814 ‐2821, 2000)

Purpose. To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods. Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results. Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion. Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.

TPS8117 Background: Improved outcomes for squamous, advanced NSCLC—beyond standard platinum doublets—have not been demonstrated. Data suggestive of response to immune therapies in squamous NSCLC support investigation in this subtype. Ipi, a fully human monoclonal antibody which binds CTLA-4, augments antitumor immune responses. Ipi improved overall survival (OS) in advanced melanoma, with side effects managed using product-specific treatment guidelines. A randomized phase II study of phased Ipi/PC (Ipi started after 2 cycles of PC) in pts with stage IV NSCLC showed significant improvement in progression-free survival (PFS), as measured by mWHO or immune-related response criteria (irRC), with a trend toward prolonged OS, over chemotherapy alone; irRC were derived from WHO criteria to better capture response patterns observed with Ipi. Improvement in PFS and OS appeared greater in tumors of squamous histology. Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. This global (~253 sites among 34 countries) phase III trial (ClinicalTrials.gov identifier NCT01285609) is investigating whether phased Ipi/PC will prolong OS in first-line pts with squamous NSCLC. Methods: Stage IV/recurrent squamous NSCLC with ECOG 0-1 will be included; pts with CNS metastases or history of autoimmune disease will be excluded. Pts are randomized to 2 cycles of PC (175 mg/m2 and AUC=6, respectively; IV), followed by 4 cycles of study drug (Ipi in Arm A, placebo in Arm B; IV) with 4 additional cycles of PC (total 6 cycles). Pts without progressive disease (PD) after induction receive maintenance therapy with blinded study drug Q12W until PD per mWHO. The study will enroll an estimated 920 pts, randomized 1:1 between arms. The primary endpoint is OS; secondary endpoints include OS among pts who receive blinded therapy, PFS, and best overall response rate. Safety is an exploratory objective of the trial. Clinical trial information: NCT01285609.

e19011 Background: The phase III BMS099 trial investigated cetuximab (C) added to taxane/carboplatin (TC) for 1st line treatment of advanced NSCLC. Progression-free survival (PFS) was not significantly different with C; response rate (RR) was significantly higher. Median overall survival (OS) was longer, with a difference not statistically significant, but similar in magnitude to the significant OS improvement from the FLEX trial (cisplat/vinorelb±C). A secondary objective of the BMS099 study was to assess the effect of C on Lung Cancer Symptoms (LCS). Methods: Chemonaïve patients (pts) with stage IIIB/IV NSCLC (any histology or EGFR expression status) were randomized to TC±C. LCS were measured using the functional assessment of cancer treatment-lung cancer subscale questionnaire (FACT-LCS), given at baseline and before each therapy cycle until disease progression (scoring 7 symptoms: breath loss, weight loss, clear thinking, coughing, appetite, chest tightness, breath ease, on a 0–4 scale). The main endpoints were rates of symptom response/progression (≥ 2 point improvement/decrease from baseline in 2 consecutive assessments), compared between arms with a stratified Cochran-Mantel-Haenszel (CMH) test; a stratified log-rank test was used to compare time to symptomatic progression. A Wei-Lachin test was used to compare between arms the changes from baseline in LCS score, and a longitudinal model was constructed to measure treatment effect on those score changes. Results: With 676 patients randomized, the baseline compliance rates for the FACT-LCS questionnaire were 99.4% and 99.1% for CTC and TC respectively, decreasing by week 18 to 74.0% and 66.4%. Baseline FACT-LCS scores were similar across treatment arms (median, 19.0). Symptom response rates were similar with CTC vs TC (32.6% vs 28.5%, CMH P=0.26), and time to symptomatic progression was not significantly different (log-rank P=0.58). Changes from baseline in FACT-LCS scores did not differ significantly between arms (Wei Lachin P=0.912; longitudinal model P=0.81). Conclusions: The addition of C to TC for the 1st treatment of advanced NSCLC resulted in similar symptom response/progression rates and did not affect trends in LCS score changes throughout treatment. [Table: see text]

9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13–18 yrs = Group B). PK analyses show linearity, with similar t1/2, clearance, and volume of distribution between groups. Irinotecan-related DLT in 2/6 pts in Group A/dose 2 necessitated dose de-escalation. Three pts experienced Grade 3 hypersensitivity infusion reaction and were discontinued. A pt with an EGFR-negative high-grade glioma (dose level 1) achieved a >70% reduction in tumor size and remains on study for 16+ months (24 cycles). A pt with ependymoma experienced a partial response (PR) and continues on cycle 12+. 9 pts received ≥4 cycles of therapy. 16 pts had a best response of stable disease or PR (mean 17 wks, range 5–66+ wks) for a clinical benefit rate of 45%. Conclusions: The combination of cetuximab and irinotecan is well-tolerated over multiple repeat cycles without cumulative toxicity in children with refractory CNS and non-CNS solid tumors. Promising preliminary anti-cancer activity was observed in a variety of pediatric solid tumors. Detailed biologic correlative and PK data will be presented. [Table: see text] No significant financial relationships to disclose.

17045 Background: Cetuximab and gefitinib inhibit the epidermal growth factor receptor (EGFR) through different mechanisms. Preclinical evidence suggests that the combination of cetuximab and Gefitinib is synergistic and has shown antitumor activity in vitro and in xenografts (Matar et al, Clin Cancer Res, 2004). We are conducting a phase I study to determine the doses of the two agents that can be administered in combination. Methods: Patients (pts) with advanced NSCLC were eligible upon progression following 1 or 2 prior chemotherapy regimens. Gefitinib was administered at a dose of 250 mg/day for all cohorts. The dose of cetuximab was escalated in sequential cohorts of patients ( table ) and there will be no dose escalation above the approved doses for both agents (dose level 3). Paraffin-embedded tissue samples of the primary cancer were collected from all patients for analysis of EGFR mutations, gene amplification and protein expression. Results: From March to December 2005, 11 patients have been entered to the 3 planned cohorts. Patient characteristics include: 3 women and 8 men, with a median age of 63 years (range 51–77) and ECOG performance status (PS) of: 0 = 50%, 1 = 50%. A total of 26 treatment cycles were administered to the 11 pts with a median of 2 cycles per pt (range 1–8). Other observed adverse events include grade 1/2 skin rash and diarrhea. Of 8 evaluable patients, 4 had stable disease. No DLT has been experienced so far at the projected recommended phase 2 dose (dose level 3). The results of correlative studies will be presented at the meeting. Conclusions: The novel combination of cetuximab and gefitinib is safe and is associated with promising anti-cancer activity in recurrent NSCLC. [Table: see text] [Table: see text]

Purpose To determine the optimal doses of the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab and the EGFR tyrosine kinase inhibitor gefitinib when administered as a combination for patients with advanced/metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Patients and Methods Patients with advanced/metastatic NSCLC treated with prior platinum-based chemotherapy received escalating doses of weekly cetuximab (100, 200, and 250 mg/m 2 , IV) and fixed doses of gefitinib (250 mg/d, PO) until disease progression or unacceptable toxicity. Available tumor samples were analyzed for EGFR expression, EGFR gene copy number and mutations, and K - RAS mutations. Results Thirteen patients were enrolled in three cohorts. Treatment was generally well-tolerated at all doses. One grade 3 headache, observed on the first treatment cycle was initially considered dose-limiting toxicity (DLT); this event was eventually determined to be caused by a brain metastasis, not toxicity. Three cases of grade 3/4 hypomagnesemia and 1 case of grade 3 skin rash occurred in the highest-dose cohort. Grade 1/2 infusion reactions occurred in three patients without requiring treatment discontinuation. Four patients (31%) achieved stable disease, no responses were observed. None of the patients had EGFR mutations or gene amplification in their tumor samples. Conclusion Dual EGFR inhibition with cetuximab and gefitinib is feasible; the combination can be safely administered and may have modest activity in advanced/metastatic NSCLC. Cetuximab 250 mg/m 2 weekly IV and gefitinib 250 mg/d PO is the recommended phase II dose, although the potential for late-onset hypomagnesemia warrants close monitoring of patients receiving this combined dosage.