TABLE 1.
Summary of PKs and E‐R information for biologics tested in GC
| Target | Molecule | Approved indication | Dose per non‐GC indication | Dose tested for GC | Patient status in pivotal clinical trial in GC | Difference in exposure for PK in GC vs. other solid tumors | Covariates on PKs | E‐R tested in GC? | E‐R at tested dose | Covariates related to E‐R | Impact on dose | Approved in GC |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HER2 | Trastuzumab 3 | HER2‐positive breast cancer; HER2‐positive metastatic G/GEJ adenocarcinoma |
q.w. Loading: 4 mg/kg Maintenance: 2 mg/kg or q3w Loading: 8 mg/kg maintenance: 6 mg/kg |
ToGA study: Loading: 8 mg/kg Maintenance: 6 mg/kg q3w Post market Heloise study: Loading: 8 mg/kg maintenance: 6 mg/kg or Loading: 8 mg/kg maintenance: 10 mg/kg |
ToGA (NCT01041404): first line locally advanced, recurrent, or metastatic GC/GEJ adenocarcinoma. HELOISE (NCT01450696): first line human EGFR2‐positive metastatic GC/GEJ adenocarcinoma. |
Predicted steady‐state AUC, Cmax, and Cmin is 30–40% lower than MBC | Body weight; prior gastrectomy; albumin levels; ethnicity; alkaline phosphatase levels | Yes |
HER2‐positive GC/GEJ: Patients with PD have lower Cmin,ss compared to patients with SD or those with objective response Overall impact reflected in a small difference in the probability of response (46% ORR in lowest quartile of exposure of 55%–64% in the three highest quartiles of exposure. Transferred to OS) |
Risk factors (ECOG PS, history of gastrectomy, Asian ethnicity, number of metastatic sites, and level of HER2 overexpression) | FDA recommended investigation of whether shortened OS within the quartile of patients with lowest Cmin is due to poor prognosis or low trastuzumab exposure. Post market HELOISE study confirmed maintenance dose increase associated with higher trastuzumab concentrations, no increased efficacy and no new safety signals. | Yes |
| Pertuzumab 4 , 8 | HER2‐positive MBC; neoadjuvant and adjuvant treatment of HER2 positive EBC |
q3w Loading: 840 mg maintenance: 420 mg |
Loading and maintenance: 840 mg q3w or Loading: 840 mg maintenance: 420 mg q3w |
Jacob (NCT01774786): first line (HER2)‐positive metastatic GC/GEJ cancer Joshua (NCT01461057): locally advanced or metastatic HER2‐positive of GC/GEJ adenocarcinoma |
Steady‐state Cmin on day 43 were 37% lower than MBC | Albumin levels; lean body weight | Yes |
HER2‐positive GC/GEJ: No differences in OS across cycle 1 pertuzumab Cmin or cycle 5 pertuzumab Cmin,ss quartiles |
Asian ethnicity, number of metastatic sites, and level of HER2 overexpression | Change dose from 840/420 mg in BC to 840 mg q3w in GC | No | |
| Trastuzumab emtansine 7 , 9 | HER2‐positive MBC; adjuvant treatment of HER2‐positive EBC |
q3w 3.6 mg/kg |
2.4 mg/kg q.w.; 3.6 mg/kg q3w | Gatsby (NCT01641939): second‐line HER2‐positive, advanced GC | Observed steady‐state AUC, Cmax, and Cmin is 20–60% lower than MBC | Body weight; serum HER2 shed ECD concentration; tumor burden | No | HER2‐positive BC: after accounting for baseline risk factors, E‐R for efficacy, demonstrated increases in T‐DM1 exposures are related to better efficacy (OS, PFS, ORR). E‐R for safety identified inverse trend for grade 3 or worse hepatotoxicity. No E‐R relationships identified for thrombocytopenia. a | NA | The higher dose: 2.4 mg/kg q.w. was tested in GC | No | |
| Trastuzumab deruxtecan 5 , 6 | 3 L unresectable or metastatic HER2‐positive breast cancer; 2 L locally advanced or metastatic HER2‐positive GC or GEJ adenocarcinoma |
q3w in BC 5.4 mg/kg |
1.6 mg/kg; 3.2 mg/kg; 5.4 mg/kg; 6.4 mg/kg; 8.0 mg/kg | DS8201‐A‐J202 (NCT03329690): second‐line+ advanced HER2+ GC/GEJ adenocarcinoma | N/A | Tumor size; country; sex; age; body weight; formulation; albumin levels; total bilirubin; aspartate aminotransferase a | No | HER2‐positive BC: significant E‐R relationship for ORR, slight trend of higher probability of PFS with higher Cmin; positive trend for higher AUC with higher risk of any grade ILD; no E‐R for nausea, diarrhea and platelet count decrease. a | No covariates were significant for exposure‐ORR relationship | Different dose approved in AGC (6.4 mg/kg q3w) vs. MBC (5.4 mg/kg q3w) patients | Yes | |
| VEGF | Ramucirumab 10 , 11 | 2 L advanced or metastatic GC or GEJ adenocarcinoma; 1 L and 2 L metastatic NSCLC；2 L mCRC； HCC | 8 mg/kg q2w; 10 mg/kg q2w; 10 mg/kg q3w | 8 mg/kg q2w |
REGARD (NCT00917384): second line and third line RAINBOW (NCT01170663): second line advanced GC/ GEJ adenocarcinoma. |
No PK difference reported across indications | Body weight; albumin levels | Yes |
GC/GEJ patients Higher ramucirumab exposures (i.e., model‐predicted Cmin values after the first dose) associated with longer median OS, PFS, and greater toxicity |
Baseline factors associated with reduced OS and PFS (REGARD): presence of peritoneal metastasis, ECOG PS of 1 or greater, and location of primary tumor (GEJ) | E‐R relationship seen in REGARD and RAINBOW led FDA to request post marketing commitment trial to test the hypothesis that higher doses of ramucirumab could be beneficial with a manageable toxicity profile | Yes |
| Bevacizumab 12 , 13 | mCRC, NSCLC, cervical cancer; glioblastoma, RCC; ovarian cancer; HCC | 5 mg/kg q2w; 10 mg/kg q2w; 7.5 mg q3w; 15 mg/kg q3w | 7.5 mg/kg q3w | AVAGAST (NCT00548548): first line – histologically confirmed, unresectable, locally advanced or metastatic GC/GEJ adenocarcinoma | CL is ~50% higher in AGC. | Body weight; albumin levels; gastrectomy | No | mCRC patients: survival proportional to the magnitude of exposure a | NA | NA | No | |
| PD1 | Pembrolizumab 14 | Melanoma; NSCLC; HNSCC; cHL; PMBCL; UC; MSI‐H or dMMR; GC; GEJ; cervical cancer: HCC; MCC; RCC; CRC; Endometrial carcinoma; TMB‐H cancer; cSCC; TNBC | i.v. infusion: 200 mg q3w or 400 mg q6w; 2 mg/kg (up to 200 mg) q3w for pediatrics | 200 mg q3w |
KN‐061 (NCT02370498): second‐line advanced GC/GEJ cancer KN‐181 (NCT02564263): second line advanced esophageal cancer; KN‐062 (NCT02494583): first‐line with advanced GC/GEJ adenocarcinoma; KN‐059 (NCT02335411): 3L+ advanced GC/GEJ adenocarcinoma |
The CL is similar to NSCLC, which was 14.5% lower than melanoma | Sex, eGFR, albumin levels, tumor burden, prior ipilimumab therapy, and ECOG‐PS on CL; sex, albumin levels, and ipilimumab prior therapy status on Vc a | No | Melanoma and NSCLC patients: Lack of dose or exposure dependency in pembrolizumab OS between 2 and 10 mg/kg a | Catabolic activity as a marker of disease severity is potentially a covariate on efficacy vs. a direct PK‐related impact | No difference in dose | Yes |
| Nivolumab 15 | Melanoma, NSCLC, malignant pleural mesothelioma, RCC, cHL, SCCHN, UC, CRC, HCC, esophageal cancer, GC, GEJ cancer, and esophageal adenocarcinoma | 240 mg q2w; 360 mg q3w; 480 mg q4w; pediatric: 3 mg/kg q2w |
CheckMate649: 360 mg q3w or 240 mg q2w; ATTRACTION‐2: 3 mg/kg q2w |
ATTRACTION‐2 (NCT02267343): patients with 2 L+ advance GC CheckMate649 (NCT02872116): first line, non‐HER2 positive GC, regardless of PD‐L1 expression |
Baseline CL is 33% higher than NSCLC | Body weight; eGFR, albumin levels; LDH; prior gastrectomy; tumor size; ECOG PS; sex; race; tumor type (GC/GEJC, or other cancer) | No |
NSCLC patients: No dose or exposure‐efficacy/safety relationship has been identified across the dose range of 3–10 mg/kg q2w a |
PD‐L1 expression level did not impact OS | No difference in dose | Yes |
Abbreviations: AGC, advanced gastric cancer; AUC, area under the curve; BC, breast cancer; cHL, classical Hodgkin lymphoma; CL, clearance; C max, maximum concentration; C min, minimum concentration; CRC, colorectal cancer; cSCC, cutaneous squamous cell carcinoma; EBC, early breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; E‐R, exposure‐response; FDA, US Food and Drug Administration; GC, gastric cancer; GEJ, gastroesophageal junction; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HNSCC, head and neck squamous cell cancer; MBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; MCC, Merkel cell carcinoma; MSI‐H or dMMR, microsatellite instability‐high (MSI‐H) or mismatch repair deficient (dMMR) solid tumors; NA, not available; NSCLC, non‐small cell lung cancer; ORR, overall response rate; OS, overall survival; PD, progression disease; PD1, programmed death‐receptor 1; PD‐L1, programmed death‐ligand 1; PFS, progression free survival; PK, pharmacokinetic; PMBCL, primary mediastinal large B‐cell lymphoma; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease; TMB‐H, tumor mutational burden‐high cancer; TNBC, triple‐negative breast cancer; UC, urothelial carcinoma; Vc, central volume of distribution; VEGF, vascular endothelial growth factor; VEGF‐A, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2.
Covariates assessment/E‐R analysis was done in other indications not GC.