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Nexavar-Tarceva Combination Therapy for First Line Treatment of Patients Diagnosed With Hepatocellular Carcinoma
Phase 3 trial testing Sorafenib (Nexavar, BAY43-9006) in Carcinoma, Hepatocellular in 732 participants. Completed in 23 May 2018.
| Lead sponsor | Bayer |
|---|---|
| Phase | Phase 3 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | double |
| Primary purpose | treatment |
| Enrollment | 732 |
| Start date | 21 May 2009 |
| Primary completion | 17 April 2012 |
| Estimated completion | 23 May 2018 |
| Sites | 127 locations across Hong Kong, Colombia, Italy, Taiwan, Poland, South Korea, New Zealand, Russia |
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18 and older, any sex, with Carcinoma, Hepatocellular. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause.
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | 289 | 250 – 321 |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | 259 | 226 – 322 |
TTP was the time from randomization to radiological tumor progression. Participants without radiological tumor progression at the time of analysis were censored at their last date of tumor evaluation. Progressive disease (PD) was defined using Response Evaluation Criteria in Solid Tumors (RECIST version 1.0), as at least a 20% increase in the sum of longest diameter (LD) of measured lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Appearance of new lesions also constituted PD.
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 97 | 82 – 126 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 122 | 88 – 136 |
Disease control was defined as the number of participants who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST assessed by magnetic resonance imaging (MRI) that was confirmed at least 28 days from the first demonstration of that rating. CR: disappearance of all clinical and radiological evidence of target and non-target tumors. PR: at least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. SD: steady state of disease. Neither sufficient shrinkage for PR nor sufficient increase for PD
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 159 | |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 188 |
The European quality of life scale (5 dimensions) (EQ-5D) questionnaire was given to the participants at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems'). The 5 health dimensions are summarized into a single score, the EQ-5D index score. The EQ-5D index score has a range of 0 and 1 with 0 representing death and 1 representing perfec
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.777 | 0.760 – 0.795 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.774 | 0.757 – 0.790 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.753 | 0.735 – 0.771 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.749 | 0.732 – 0.766 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.728 | 0.708 – 0.748 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.724 | 0.706 – 0.743 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.704 | 0.681 – 0.726 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.700 | 0.678 – 0.721 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.679 | 0.653 – 0.705 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.675 | 0.650 – 0.700 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 0.654 | 0.625 – 0.684 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 0.651 | 0.622 – 0.679 |
Participants indicated on a scale of 0 (worst) to 100 (best) how good or bad their health state was on that particular day.
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 74.397 | 73.219 – 75.576 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 74.656 | 73.504 – 75.808 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 72.649 | 71.420 – 73.877 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 72.907 | 71.735 – 74.080 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 70.900 | 69.518 – 72.281 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 71.158 | 69.854 – 72.462 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 69.151 | 67.542 – 70.759 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 69.409 | 67.891 – 70.927 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 67.402 | 65.520 – 69.283 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 67.660 | 65.875 – 69.445 |
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 65.653 | 63.468 – 67.837 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 65.911 | 63.827 – 67.996 |
Duration of response - RECIST: number of days from the date that CR or PR is first documented to date that PD is first objectively documented or to death before progression. Note: the relevant date is that of the first documentation, not the confirmation date (if participant progressed or died then censored=no) or to last observation if participant did not progress or die then censored=yes note: this last observation date should be the same as that used for time to progression.
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 297 | 100 – 427 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 168 | 90 – NA |
Time to response was the number of days from randomization to the date the CR or PR was documented (with confirmation) (Note: the relevant date is that of the first documentation, not the confirmation date).
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 84.5 | 47 – 122 |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 83.5 | 39 – 331 |
Tumor response was the proportion of participants with the best tumor response (ie, achieving either a confirmed complete response \[CR\] or partial response \[PR\], according to Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria).
| Group | Value | 95% CI |
|---|---|---|
| Sorafenib (Nexavar, BAY 43-9006) + Erlotinib (Tarceva) | 24 | |
| Sorafenib (Nexavar, BAY 43-9006) + Placebo | 14 |
Time frame: From start of treatment up to 30 days after the last dose of study medication. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Sorafenib (Nexavar, BAY43-… | Sorafenib (Nexavar, BAY43-… |
|---|---|---|---|
| Liver dysfunction | Hepatobiliary disorders | — | — |
| Liver dysfunction | Hepatobiliary disorders | — | — |
| Death not associated with CTCAE term, Disease progression NOS | General disorders | — | — |
| Constitutional symptoms - Other | General disorders | — | — |
| Constitutional Symptoms - Other | General disorders | — | — |
| Death not associated with CTCAE term, Disease Progression NOS | General disorders | — | — |
| Pain, Abdomen NOS | General disorders | — | — |
| Ascites | Gastrointestinal disorders | — | — |
| Diarrhea | Gastrointestinal disorders | — | — |
| Diarrhea | Gastrointestinal disorders | — | — |
| Pain, Abdomen NOS | General disorders | — | — |
| Ascites | Gastrointestinal disorders | — | — |
| Dehydration | Gastrointestinal disorders | — | — |
| Fever | General disorders | — | — |
| Bilirubin (Hyperbilirubinemia) | Metabolism and nutrition disorders | — | — |
| Hemorrhage, GI, Varices (Esophageal) | Vascular disorders | — | — |
| Dehydration | Gastrointestinal disorders | — | — |
| Fever | General disorders | — | — |
| Bilirubin (hyperbilirubinemia) | Metabolism and nutrition disorders | — | — |
| Hemorrhage, GI, Upper GI NOS | Vascular disorders | — | — |
| Fatigue | General disorders | — | — |
| Hemorrhage, GI, Upper GI NOS | Vascular disorders | — | — |
| Hemorrhage, GI, Varices (esophageal) | Vascular disorders | — | — |
| Fatigue | General disorders | — | — |
| No code in CTCAE | General disorders | — | — |
| Reaction | System | Sorafenib (Nexavar, BAY43-… | Sorafenib (Nexavar, BAY43-… |
|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | — | — |
| Diarrhea | Gastrointestinal disorders | — | — |
| Fatigue | General disorders | — | — |
| Fatigue | General disorders | — | — |
| Rash/desquamation | Skin and subcutaneous tissue disorders | — | — |
| Rash/desquamation | Skin and subcutaneous tissue disorders | — | — |
| Hand-foot skin reaction | Skin and subcutaneous tissue disorders | — | — |
| Hand-foot skin reaction | Skin and subcutaneous tissue disorders | — | — |
| Anorexia | Gastrointestinal disorders | — | — |
| Anorexia | Gastrointestinal disorders | — | — |
| Weight loss | General disorders | — | — |
| Weight loss | General disorders | — | — |
| Pain, Abdomen NOS | General disorders | — | — |
| Nausea | Gastrointestinal disorders | — | — |
| Pain, Abdomen NOS | General disorders | — | — |
| Nausea | Gastrointestinal disorders | — | — |
| Ascites | Gastrointestinal disorders | — | — |
| Hypertension | Cardiac disorders | — | — |
| Hypertension | Cardiac disorders | — | — |
| Ascites | Gastrointestinal disorders | — | — |
| Alopecia | Skin and subcutaneous tissue disorders | — | — |
| Alopecia | Skin and subcutaneous tissue disorders | — | — |
| Edema: Limb | Blood and lymphatic system disorders | — | — |
| Edema: Limb | Blood and lymphatic system disorders | — | — |
| Vomiting | Gastrointestinal disorders | — | — |
| Vomiting | Gastrointestinal disorders | — | — |
| AST | Metabolism and nutrition disorders | — | — |
| Constipation | Gastrointestinal disorders | — | — |
| AST | Metabolism and nutrition disorders | — | — |
| Bilirubin (Hyperbilirubinemia) | Metabolism and nutrition disorders | — | — |
| Bilirubin (hyperbilirubinemia) | Metabolism and nutrition disorders | — | — |
| Mucositis (functional/symptomatic), Oral cavity | Gastrointestinal disorders | — | — |
| Constipation | Gastrointestinal disorders | — | — |
| Mucositis (functional/symptomatic), Oral cavity | Gastrointestinal disorders | — | — |
| Fever | General disorders | — | — |
| Fever | General disorders | — | — |
| Hemoglobin | Blood and lymphatic system disorders | — | — |
| Hemorrhage pulmonary, Nose | Vascular disorders | — | — |
| Hemoglobin | Blood and lymphatic system disorders | — | — |
| Hemorrhage pulmonary, Nose | Vascular disorders | — | — |
Most-reported serious reactions: Liver dysfunction, Liver dysfunction, Death not associated with CTCAE term, Disease progression NOS, Constitutional symptoms - Other, Constitutional Symptoms - Other, Death not associated with CTCAE term, Disease Progression NOS, Pain, Abdomen NOS, Ascites.
Data from ClinicalTrials.gov NCT00901901 adverse events section.
This is a randomized trial to evaluate the clinical benefit of sorafenib 400 mg twice daily and erlotinib 150 mg once a day versus sorafenib 400 mg twice daily and placebo erlotinib once daily in subjects with unresectable advanced or metastatic Child-Pugh A HCC. Patients who are candidates for potentially curative intervention (i.e. surgical resection or local ablation) are not eligible for this study.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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