Inclusion criteria require confirmed advanced solid tumors across multiple indications (NSCLC, breast cancers, HNSCC, etc.), age ≥18, ECOG 0-1, measurable disease by RECIST v1.1, adequate organ function (hematologic/hepatic/renal), and QTcF <470 msec. Exclusions include active CNS metastases, uncontrolled CV disease, unresolved toxicity (>Grade 1), prior EDB+FN therapy, high-risk infections (HBV/HCV/HIV), recent anticancer therapy (28 days), and visual/corneal impairments. Safety monitoring continues in Part 2 (AEs up to 2 years).

This segment covers safety assessments for Part 1, including Dose-Limiting Toxicities (DLTs) defined by protocol-specific criteria occurring within the first 21 days of treatment, and adverse events (AEs) monitored for approximately 3 years with grading based on NCI-CTCAE v5.0. It also introduces Objective Response Rate (ORR) in Part 2 as a key efficacy endpoint evaluated up to 2 years.

This section details pharmacokinetic parameters (Cmax, Tmax, CL, AUC0-t, AUCtau, AUC0-inf, t½) for PYX-201 components in Part 1, measured over 2 years, alongside clinical response metrics (ORR, DOR, PFS, DCR, TTR, OS) with follow-up to 3 years. Part 2 data includes efficacy endpoints (DOR, CBR, mPFS, DCR, TTR, mOS) and drug concentration measures (Cmax, Tmax, trough levels), extending observation to approximately 4 years for survival outcomes.

Inclusion criteria require advanced solid tumors (HNSCC, TNBC, HR+/HER2- BC, GC, cervical cancer), age ≥18, ECOG PS 0-1, measurable disease per RECIST v1.1, life expectancy >3 months, and adequate organ function. Exclusion criteria include active CNS metastases, uncontrolled infections (HBV/HCV/HIV), unresolved prior toxicities (>Grade 1), autoimmune disease, prior PD-1/L1 inhibitors, and severe hypersensitivity to study drugs or excipients. Strict eligibility ensures patient safety and measurable efficacy assessment.

Experimental: Part 1: Dose Escalation, Participants will receive escalating doses of PYX-201 to evaluate the safety, tolerability, and preliminary efficacy of PYX-201 in combination with pembrolizumab.Experimental: Part 2: Dose Expansion, Part 2 dose-expansion cohorts will be opened based on emerging data to further inform the safety, tolerability, and preliminary efficacy determinations as defined.

This segment outlines efficacy and pharmacokinetic assessments, evaluating Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Time to Response, and Clinical Benefit Rate (CBR) over ~2 years. Pharmacokinetic analysis includes Cmax, Tmax, Clearance (CL), AUC (0-t, tau, and 0-inf), half-life (t½) for ADC, total antibody, and free payload, along with immunogenicity assessment via anti-drug antibodies.

A total of 18 pts were enrolled in three dose cohorts: gedatolisib 110 mg weekly cofetuzumab pelidotin 1.40 mg/kg every 3 weeks (n=4), 180 mg, 1.40 mg/kg (n=3), and 180 mg, 2.80 mg/kg (n=11). Nausea, anorexia, fatigue, and mucositis were common but rarely reached grade 3 severity. Myelosuppression was uncommon. ORR was 16.67% (3/18). An additional 3 pts had stable disease (of these 2 had stable disease for>18 weeks); CB18 was 27.80%. Median PFS was 2.00 months (95% confidence interval for PFS: 1.20-6.20). Pts with clinical benefit were enriched with genomic alterations in the PI3K and PTK7 pathways.

The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia,fatigue, headache, neutropenia, and vomiting (45%); 25% of patients had grade 3 neutropenia. Two patients experienced doselimiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.80 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27.00% in ovarian cancer (n=63), 19% in NSCLC (n=31), and 21% in TNBC (n=29).

Inclusion criteria for Q3W: advanced/metastatic solid tumors refractory to standard therapy, ECOG PS 0-1, adequate organ function; Part 2 targeted ovarian cancer (OVCA), TNBC, and NSCLC. Q2W included platinum-resistant OVCA (≤2 prior lines) or recurrent NSCLC (≤3 prior lines), ECOG PS 0-2. Exclusions: non-epithelial OVCA, active CNS metastases, unresolved bowel obstruction, recent anticancer therapy (4 weeks), or active infections. Both regimens excluded patients with significant comorbidities (uncontrolled infections, recent major surgery/radiation).

This section details safety assessments for PF-06647020 across Q3W (every 3 weeks) and Q2W (every 2 weeks) regimens, monitoring dose-limiting toxicities (DLTs) during initial treatment cycles (21 days for Q3W, 28 days for Q2W) including hematologic (Grade 4 neutropenia, febrile neutropenia), hepatic (Grade ≥3 bilirubin/transaminases), and non-hematologic toxicities. Treatment-emergent adverse events (AEs), graded per NCI CTCAE v4.03, were tracked for up to 32 months (Q3W) or 19 months (Q2W), with lab abnormalities (hematology, chemistry, urinalysis, coagulation) analyzed for shifts from baseline to Grade ≥3.

Pharmacokinetic (PK) parameters (AUCtau, Cmax, CL, Vss, t1/2, Rac, Tmax, AUClast, AUCinf) were evaluated for PF-06647020, its metabolites (PF-06380101, hu6M024 mAb), and dose-normalized values in DDI sub-studies under Q3W (504-hour tau) and Q2W (336-hour tau) regimens. Efficacy endpoints included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to progression (TTP), and progression-free survival (PFS), assessed per RECIST v1.1 via tumor imaging every 6-8 weeks. Immunogenicity (anti-drug antibodies [ADA]/neutralizing antibodies [NAb]) was monitored for ~31 months (Q3W) or 18 months (Q2W).

Inclusion criteria require histologically confirmed PTK7-expressing NSCLC, progression after platinum-based therapy +/- targeted agents (≤2 prior lines [≤3 if targeted]), ECOG 0-1, measurable disease, and adequate organ function. Exclusions include active CNS metastases (unless treated/asymptomatic for ≥2 weeks), unresolved Grade ≥2 toxicity (except alopecia/anaemia), significant comorbidities, recent anticancer therapy (within 28 days, except palliative RT ≤10 fractions), or herbal therapies within 7 days.

This section defines Dose-limiting Toxicities (DLT) assessed during Part 1 over 21 days, categorized into hematologic (Grade 4 neutropenia >7 days, febrile neutropenia, thrombocytopenia with bleeding) and non-hematologic (Grade ≥3 toxicities, treatment delays >2 weeks). It also outlines Objective Response criteria (complete/partial response) based on RECIST v1.1 for Part 1 and 2, covering target/non-target lesion assessments every 6 weeks until progression or 3 years.

This segment details Treatment-Emergent Adverse Events (TEAEs) over 3 years, including serious AEs (death, hospitalization, disability), lab abnormalities (hematology, chemistry, urinalysis), and vital signs criteria (BP, pulse rate). Pharmacokinetic parameters (Cmax, Tmax, AUCtau, CL, Vss, t1/2) for ADC components are provided, along with anti-drug antibody (ADA) testing and survival metrics (PFS, OS) for Part 2.

In cell line xenograft (CLX) studies, nude mice were injected subcutaneously in the flank with suspensions of 10 x10⁶ BT474 cells, in 50% Matrigel (BD Biosciences). Mice were randomized into study groups when tumors reached approximately 150-300 mm³. Either PBS (Gibco, catalog no., 14190-144, as vehicle), PF-06804103, or PT-DM1 at different doses was administered intravenously starting on day 0 for a total of four doses, 4 days apart (four times every 4 days).

In cell line xenograft (CLX) studies, nude mice were injected subcutaneously in the flank with suspensions of 1 x10⁶ NCI-N87, in 50% Matrigel (BD Biosciences). Mice were randomized into study groups when tumors reached approximately 150-300 mm³. Either PBS (Gibco, catalog no., 14190-144, as vehicle), PF-06804103, or PT-DM1 at different doses was administered intravenously starting on day 0 for a total of four doses, 4 days apart (four times every 4 days).

Inclusion criteria cover HER2+/- breast/gastric cancer (Part 1A/B, Part 2A/B) resistant to standard therapy, with PS 0-1 and adequate organ function. Exclusions include CNS metastases, anthracycline overdose, Grade 3+ antibody hypersensitivity, active infections, LVEF <50%, or interstitial lung disease. Eligibility is tailored by study part, emphasizing safety and biomarker relevance.

This multi-center, open-label, first-in-patient, phase I study (NCT03284723) has two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, groups of adult patients (pts) with HER2+ BC or HER2+ GC, who are resistant or intolerant to standard therapy or for which no standard therapy is available, received PF-06804103 intravenously once every 21 days (Q3W); dosage was escalated per cohort. Primary objectives were to evaluate the safety and tolerability of PF-06804103, characterize its dose-limiting toxicities (DLTs), and determine the recommended phase 2 dose.

This section outlines Dose-Limiting Toxicities (DLTs) observed in Part 1A (21-day cycle) and Part 1B (28-day cycle) during the first treatment cycle, categorizing them into hematologic (Grade 4 neutropenia >7 days, febrile neutropenia, thrombocytopenia with bleeding) and non-hematologic (Grade ≥3 toxicities, treatment delays, liver abnormalities). It also details Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), including definitions and timeframes (up to 89.3 weeks for Part 1A, 53.7 weeks for Part 1B). Laboratory abnormalities (hematology, chemistry, urinalysis) and vital sign criteria are summarized, along with response metrics (Objective Response, Duration of Response, PFS, TTP) in Part 2, all assessed per RECIST v1.1.

This segment focuses on clinical outcomes in Part 1 (Objective Response, DR, PFS, TTP) with assessment intervals every 6 (Part 1A) or 8 weeks (Part 1B). Immunogenicity (anti-drug antibodies) and HER2 tumor analysis are included. Pharmacokinetic parameters (Cmax, t1/2, AUCinf, AUCtau, CL, Vss, Rac) for PF-06804103 ADC, total antibody, and unconjugated payload (PF-06380101) are detailed, with data from Part 1A/B (sparse sampling excluded Part 2A). Key metrics like terminal half-life, clearance, and volume of distribution are calculated per dosing intervals (504h for Part 1A, 336h for Part 1B).