How Effective Is Erlotinib for Lung Cancer?

Can be used for third-line treatment of locally advanced or metastatic non-small cell lung cancer with two or more chemotherapy regimens, based on the results of a phase III clinical study abroad. This product must be used under the guidance of a doctor with experience in the use of such drugs, and only used in national clinical trial pharmacological bases or tertiary A hospitals.

Drug Name: Erlotinib
Alias: Erlotinib hydrochloride tablets
Main indications: Non-small cell lung cancer

Dosage: 150mg / day
Adverse reactions: Rash, diarrhea
Main medication contraindications: Use with caution in patients with abnormal liver function

Erlotinib drug name

Common name: Erlotinib hydrochloride tablets Trade name: Tarceva

English: Tarceva

English name: Erlotinib Hydrochloride Tablets

Phonetic script ( Hanyu Pinyin): Yansuan Eluotini Pian

Erlotinib ingredients

The main ingredient of this product is erlotinib hydrochloride.

Chemical Name:

Erlotinib N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinolinamine hydrochloride

Chemical Structure:

Molecular formula: C22H23N3O4 · HCl

Molecular weight: 429.90

Erlotinib indications

Erlotinib can be used as a third-line treatment for locally advanced or metastatic non-small cell lung cancer with two or more chemotherapy regimens. This indication is based on the results of a phase III clinical study abroad.

The efficacy of second-line treatment for Chinese non-small cell lung cancer remains to be confirmed by further clinical studies.

First-line treatment of locally advanced or metastatic NSCLC patients in two multicenter, placebo-controlled, randomized phase III trials. Results show concurrent erlotinib in platinum-based chemotherapy (carboplatin + paclitaxel; or gemcitabine + cisplatin) There is no clinical benefit and therefore is not recommended for first-line treatment of the above conditions.

Erlotinib specifications

25 mg

25mg tablets: round, biconvex, white-coated tablets with orange "Tarceva", "25" and the Tarceva logo printed on one side and blank on the other side.

100 mg

100mg tablets: round, biconvex, white-coated tablets with gray "Tarceva", "100", and the Tarceva logo printed on one side and blank on the other.

CD150 mg

150mg tablets: round, biconvex, white-coated tablets with brown "Tarceva", "150" and the Tarceva logo printed on one side and blank on the other side.

Erlotinib

Erlotinib dosage

This product must be used under the guidance of a doctor with experience in the use of such drugs, and only used in national clinical trial pharmacological bases or tertiary A hospitals.

The recommended dose of erlotinib monotherapy for non-small cell lung cancer is 150 mg / day, taken at least 1 hour before or 2 hours after eating. Continue medication until disease progression or intolerable toxicity. There is no evidence that patients can benefit from continuing treatment after progression.

Dose adjustment

Patients with new acute attacks or progressive pulmonary symptoms, such as dyspnea, cough, and fever, should be suspended for erlotinib treatment for diagnostic evaluation. If the diagnosis is ILD (interstitial lung disease), erlotinib should be discontinued and appropriate treatment given (see [Caution] Warning-Lung Toxicity).

Diarrhea is usually controlled with loperamide. Patients with severe diarrhea loperamide who are ineffective or dehydrated require dose reductions and temporary discontinuation of treatment. Patients with severe skin reactions also require dose reductions and temporary discontinuation of treatment.

If a reduction is necessary, erlotinib should be reduced by 50 mg at a time.

Concurrent use of CYP3A4 strong inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, Dose reductions should be considered for drugs such as telithromycin, aceandromycin (TAO), and voriconazole, or serious adverse events may occur.

The use of CYP3A4 inducer rifampicin before treatment can reduce the AUC of erlotinib by 2/3. Alternative treatments without CYP3A4 inducing activity should be considered. If there is no alternative treatment, a dose of erlotinib greater than 150 mg should be considered. If the dose of erlotinib is increased, the dose should be reduced when stopping rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentin, phenytoin, carbamazepine, phenobarbital, and St. John's wort, these drugs should be avoided if possible (see [Cautions] and [Drugs interaction).

Erlotinib clearance in liver metabolism and biliary secretion. Erlotinib should be used with caution in patients with liver dysfunction. If serious adverse reactions occur, erlotinib reduction or suspension should be considered (see [Pharmacokinetics] special population-patients with abnormal liver function, [cautions] patients with abnormal liver function and [adverse reactions]).

Erlotinib adverse reactions

The safety data came from 856 cancer patients treated with erlotinib monotherapy abroad, 308 patients receiving erlotinib 100 or 150 mg combined with gemcitabine for pancreatic cancer, and 1,228 patients treated with erlotinib concurrently with chemotherapy.

Serious adverse events, including fatal ones, have been reported in patients taking erlotinib for NSCLC, pancreatic cancer, and other advanced solid tumors (see [Caution] Warning-Pulmonary Toxicity and [Dosage Adjustment] Dosage Adjustment).

Non-small cell lung cancer (NSCLC)

A randomized double-blind placebo-controlled trial BR.21 was performed in 731 patients with locally advanced or metastatic NSCLC who had failed at least one chemotherapy regimen in 17 countries. Patients were randomized to receive erlotin once daily at a ratio of 2: 1. 150 mg or placebo until disease progression or unacceptable toxicity.

Regardless of cause, the most common adverse reactions were rash (75%) and diarrhea (54%). It is mostly 1 degree or 2 degrees, and can be processed without interrupting medication. Erlotinib-treated patients had 9% and 6% of rash and diarrhea of 3/4 degree, respectively. 1% of erlotinib-treated patients discontinued the trial due to rash or diarrhea. Rash and diarrhea require reduction in 6% and 1% of patients, respectively. The median time to rash in BR.21 was 8 days, and the median time to diarrhea was 12 days.

In BR.21, adverse events occurred in at least 10% of patients in the erlotinib group, which was higher (3%) than in the placebo group. The NCI-CTC classification summary is shown in Table 1. Listed are adverse reactions that the sponsor assessed as being associated with erlotinib treatment.

Table 1: Adverse events in the erlotinib group with a higher incidence (3%) and a incidence of 10% in the BR.21 study

Erlotinib N = 485 Placebo N = 242

NCI-CTC grade any 3 degrees 4 degrees any 3 degrees 4 degrees

Adverse Drug Reaction Terms%%%%%%

Total patients with AE 99 40 22 96 36 22

Infection and infection

Infection * 24 4 0 15 2 0

Metabolic and nutritional disorders

Decreased appetite 52 8 1 38 5 <1

Eye disease

Conjunctivitis 12 <1 0 2 <1 0

Dry keratoconjunctivitis 12 0 0 3 0 0

Respiratory, chest, and mediastinal abnormalities

Dyspnea 41 17 11 35 15 11

Cough 33 4 0 29 2 0

Gastrointestinal disorders

Diarrhea 54 6 <1 18 <1 0

Nausea 33 3 0 24 2 0

Vomiting 23 2 <1 19 2 0

Stomatitis 17 <1 0 3 0 0

Abdominal pain 11 2 <1 7 1 <1

Abnormal skin and subcutaneous tissue

Rash 75 8 <1 17 0 0

Itching 13 <1 0 5 0 0

Dry skin 12 0 0 4 0 0

General discomfort and medication site conditions

Fatigue 52 14 4 45 16 4

* Severe infection with or without neutrophil deficiency, including pneumonia, sepsis, and cellulitis.

Abnormal liver function tests (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin) were observed in patients with NSCLC treated with erlotinib 150 mg monotherapy. The increase is mainly transient or related to liver metastases. Erlotinib and placebo-treated patients experienced a 2 degree increase in ALT (> 2.5 to 5.0 times the upper limit of normal) of 4% and <1%, respectively. Erlotinib-treated patients did not experience a 3-degree ALT elevation (> 5.0 to 20.0 times the upper limit of normal). When liver function is abnormal, dose reduction or suspension of treatment should be considered (see [Dosage Adjustment] for dosage).

Pancreatic cancer

The most common adverse reactions in pancreatic cancer patients treated with 100 mg erlotinib + gemcitabine were fatigue, rash, nausea, loss of appetite, and diarrhea. In the erlotinib + gemcitabine treatment group, the incidence of 3/4 degree rash and diarrhea in the treated patients was 5% each, and the median time was 10 days and 15 days, respectively, leading to a reduction in 2% of patients Treatment, no more than 1% of patients discontinued.

Certain adverse reactions in the 150 mg group (23 patients), including higher incidence of rashes, and even more frequent reductions or withdrawals.

In the key study PA.3, adverse events occurred in at least 10% of patients in the 100 mg erlotinib + gemcitabine treatment group, and the incidence of adverse reactions was higher than in the placebo + gemcitabine group (3%). See Table 2. Listed are adverse reactions that the sponsor assessed as being associated with erlotinib treatment.

Table 2: Adverse events at a rate of 10% in the 100 mg erlotinib + gemcitabine treatment group in the PA.3 study and higher (3%) adverse events than in the placebo + gemcitabine treatment group

Erlotinib + Gemcitabine

1000mg / IV, N = 259 placebo + gemcitabine

1000mg / IV, N = 256

NCI-CTC grade any 3 degrees 4 degrees any 3 degrees 4 degrees

Adverse Drug Reaction Terms%%%%%%

Fatigue 73 14 2 70 13 2

Rash 69 5 0 30 1 0

Nausea 60 7 0 58 7 0

Decreased appetite 52 6 <1 52 5 <1

Diarrhea 48 5 <1 36 2 0

Abdominal pain 46 9 <1 45 12 <1

Vomiting 42 7 <1 41 4 <1

Weight loss 39 2 0 29 <1 0

Infection * 39 13 3 30 9 2

Edema 37 3 <1 36 2 <1

Fever 36 3 0 30 4 0

Constipation 31 3 1 34 5 1

Bone pain 25 4 <1 23 2 0

Dyspnea 24 5 <1 23 5 0

Oral mucositis 22 <1 0 12 0 0

Myalgia 21 1 0 20 <1 0

Depression 19 2 0 14 <1 0

Indigestion 17 <1 0 13 <1 0

Cough 16 0 0 11 0 0

Stun 15 <1 0 13 0 <1

Headache 15 <1 0 10 0 0

Insomnia 15 <1 0 16 <1 0

Hair loss 14 0 0 11 0 0

Anxiety 13 1 0 11 <1 0

Neuropathy 13 1 <1 10 <1 0

Flatulence 13 0 0 9 <1 0

Chills 12 0 0 9 0 0

* Severe infection with or without neutrophil deficiency, including pneumonia, sepsis, and cellulitis.

In clinical trials of pancreatic cancer, deep vein thrombosis occurred in 10 patients (3.9%) in the erlotinib / gemcitabine group. In contrast, deep vein thrombosis occurred in 3 patients in the placebo / gemcitabine group (incidence rate 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep vein thrombosis, was similar in the two treatment groups: 11% in the erlotinib + gemcitabine group and 9% in the placebo + gemcitabine group.

There was no difference in 3 or 4 degree hematology laboratory toxicity in the erlotinib + gemcitabine group compared with the placebo + gemcitabine group.

Severe adverse events (NCI-CTC grade 3) in the erlotinib + gemcitabine group that included syncope, arrhythmia, intestinal obstruction, pancreatitis, hemolytic anemia including microvascular hemolysis caused by thrombocytopenia Anemia, myocardial infarction / myocardial ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency (see [Caution] warning).

Abnormal liver function tests (including elevated ALT, AST, and bilirubin) were observed in patients with pancreatic cancer treated with erlotinib + gemcitabine. Table 3 lists the most severe NCI-CTC liver function abnormalities that occurred. If liver function changes are serious, you should consider reducing the dose of erlotinib or discontinuing the drug (see the [Usage and Dosage] dose adjustment section).

Table 3: Abnormal liver function test in pancreatic cancer treated patients (most severe NCI-CTC classification): 100mg group

Erlotinib + Gemcitabine

1000mg / IV, N = 259 placebo + gemcitabine

1000mg / IV, N = 256

NCI-CTC classification 2 degrees 3 degrees 4 degrees 2 degrees 3 degrees 4 degrees

Bilirubin 17% 10% <1% 11% 10% 3%

ALT 31% 13% <1% 22% 9% 0%

AST 24% 10% <1% 19% 9% 0%

Other observations (based on all clinical research data)

Safety data were obtained from more than 800 patients who received at least one dose of 150 mg erlotinib monotherapy, and more than 300 patients who received erlotinib 100 or 150 mg in combination with gemcitabine.

The following adverse reactions were observed in patients receiving erlotinib 150 mg monotherapy or erlotinib 100 mg or 150 mg in combination with gemcitabine.

The following terms are used to rank the incidence of adverse reactions: very common (1 / 10); common (1 / 100, <1/10); uncommon (1 / 1,000, <1/100); Rare (1 / 10,000, <1/1000); very rare (<1 / 10,000), including individual reports.

Very common adverse reactions are shown in Tables 1 and 2. The classification of adverse reactions at other frequencies is summarized below.

Gastrointestinal disorders:

Common gastrointestinal bleeding has been reported in the NSCLC trial and pancreatic cancer combined drug trials, some of which are related to concurrent use of warfarin or non-steroidal anti-inflammatory drugs (see [Notes] Increase in international standardized ratio and possible bleeding) . These reports include gastrointestinal ulcer bleeding (gastritis, stomach and duodenal ulcers), hemoptysis, blood in the stool, melena, and possible colitis bleeding (see [Notes]).

Abnormal liver function:

Erlotinib is often observed in clinical trials for abnormal liver function tests (including elevated ALT, AST, and bilirubin), and is particularly common in PA3 studies. Most are mild to moderate, transient or related to liver metastases. Rare cases of liver failure (including death) have been reported during erlotinib use. Confounding factors include pre-existing liver disease or concomitant hepatotoxic drugs.

Eye disease:

Keratitis often occurs in clinical trials of erlotinib. Conjunctivitis often occurs in trials of pancreatic cancer.

Corneal ulcers are very rare and are a complication of mucosal inflammation in patients receiving erlotinib.

Respiratory, chest, and mediastinal abnormalities:

When erlotinib is used to treat NSCLC and other progressive solid tumors, patients have reported severe interstitial lung disease (ILD) -like events including death (see Precautions).

Allergic rhinitis has been reported in NSCLC and pancreatic cancer trials.

Abnormal skin and subcutaneous tissue:

Dry skin is common in tests for pancreatic cancer. Hair loss is common in trials of NSCLC.

Overall, the safety of erlotinib was not significantly different between women and men, and between young people and those over 65 years of age, either in monotherapy or in combination with gemcitabine. There is no difference between them (see [Precautions] and [Medication for the Elderly]).

Erlotinib Taboo

Those who are allergic to this product and its ingredients are prohibited.

Erlotinib precautions

This product must be used under the guidance of a doctor with experience in the use of such drugs, and only used in the National Oncology Drug Clinical Trial Base or a tertiary hospital.

Erlotinib may have clinically significant drug interactions.

caveat

Pulmonary toxicity

Patients receiving erlotinib for NSCLC, pancreatic cancer, or other solid tumors have occasionally reported severe interstitial lung-like events, including fatal conditions. In randomized monotherapy NSCLC trials (see [Clinical Trials]), the incidence of interstitial lung disease-like events (0.8%) was the same in the erlotinib and placebo groups. In the treatment of pancreatic cancer trials-in combination with gemcitabine (see [Clinical Trials]), the incidence of interstitial lung disease-like events was 2.5% in the erlotinib + gemcitabine group and 0.4% in the placebo + gemcitabine group.

The total incidence of 4900 erlotinib-treated patients in all trials (including trials without a control group and trials with concurrent chemotherapy) was approximately 0.6%. Diagnosis reports for patients suspected of interstitial lung disease-like events include pneumonia, radiation pneumonitis, allergic pneumonia, interstitial pneumonia, interstitial lung disease, occlusive bronchitis, pulmonary fibrosis, acute respiratory distress syndrome, lung Infiltration and alveolitis. Symptoms can occur from 5 to 9 months (median 39 days) after taking erlotinib. Most cases are complicated by other factors that cause interstitial lung disease, such as concurrent or previous chemotherapy, previous radiation therapy, pre-existing interstitial lung disease, metastatic lung disease, or lung infection.

In the event of a new acute attack or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, erlotinib treatment should be temporarily stopped during diagnostic evaluation. Once diagnosed as ILD (interstitial lung disease), stop erlotinib treatment if necessary and give appropriate treatment (see [Adverse Reactions] and [Dosage and Administration]).

Diarrhea, dehydration, electrolyte imbalance, and renal failure

Patients receiving erlotinib may develop diarrhea, and moderate or severe diarrhea should be treated with loperamide. Some patients may need to reduce the dose. For severe or persistent dehydration-related diarrhea, nausea, anorexia or vomiting, patients need to discontinue medication and take appropriate treatment measures for dehydration (see [Adverse Reactions]). Rarely, severe dehydration with hypokalemia and renal failure (including fatal) occurs, mainly in patients receiving concurrent chemotherapy. For patients with severe or persistent diarrhea, or even dehydration, especially those with high risk factors (eg, patients receiving concurrent chemotherapy, other symptoms or diseases, or other underlying factors including older age) The treatment of erlotinib should be discontinued and appropriate measures should be taken for intravenous fluid replacement in patients. At the same time of fluid replacement, patients were monitored for renal function and blood electrolytes including potassium.

Myocardial infarction / myocardial ischemia

In a clinical trial of pancreatic cancer, myocardial infarction / myocardial ischemia occurred in 6 patients (2.3%) in the erlotinib / gemcitabine group, and 1 patient died of myocardial infarction. In contrast, three patients in the placebo / gemcitabine group had myocardial infarction (1.2% incidence), and one of them died of myocardial infarction.

Cerebrovascular accident

In clinical trials of pancreatic cancer, cerebrovascular accidents occurred in 6 patients (2.3%) in the erlotinib / gemcitabine group, with bleeding once and the only fatal event. In contrast, there were no cerebrovascular accidents in the placebo / gemcitabine group.

Microvascular hemolytic anemia caused by thrombocytopenia

In a clinical trial of pancreatic cancer, microvascular hemolytic anemia caused by thrombocytopenia occurred in two patients (occurrence rate: 0.8%) in the erlotinib / gemcitabine group. Both patients used erlotinib and gemcitabine simultaneously. In contrast, microvascular hemolytic anemia due to thrombocytopenia did not occur in the placebo / gemcitabine group.

Hepatitis, liver failure

Rare cases of liver failure (including death) have been reported during erlotinib use. Confounding factors include pre-existing liver disease or concomitant hepatotoxic drugs. Therefore, these patients should have regular liver function tests. Patients with severe liver dysfunction should stop taking erlotinib (see [Adverse Reactions]).

Patients with abnormal liver function

Both in vitro and in vivo experiments have demonstrated that erlotinib is primarily cleared in the liver. Therefore, exposure to erlotinib is increased in patients with liver dysfunction (see [Pharmacokinetics] Special Populations-Patients with liver dysfunction and [Dosage and Administration] dose adjustment).

Increased international standardization ratio and possible bleeding

Clinical trials have reported increased international standardized ratio (INR) and rare bleeding events, including gastrointestinal and parenteral bleeding, some of which are related to the simultaneous use of warfarin. Patients taking warfarin or other dicoumarin anticoagulants should regularly monitor prothrombin time or INR (see [Adverse Reactions]).

[Medication for pregnant and lactating women]

Pregnancy class D

Erlotinib has not been studied adequately in pregnant women. Animal studies have shown some reproductive toxicity. The potential dangers to humans are unknown. Women of childbearing age should avoid pregnancy while taking erlotinib. Adequate contraception during treatment and at least 2 weeks after treatment is complete. Only pregnant women who believe that the benefits of the mother outweigh the harm to the fetus can continue treatment. If erlotinib is used during pregnancy, patients should be aware of the potential harm to the fetus and the potential for miscarriage.

It is unclear whether erlotinib is secreted from human milk. Because many drugs are secreted into human milk and the effects of erlotinib on infants have not been studied, it is recommended that women avoid breastfeeding when using erlotinib.

[Child medication]

Efficacy and safety studies of erlotinib have not been performed in children.

[Medicine for the elderly]

Of the total population participating in the NSCLC randomized trial, 62% of patients were younger than 65 years of age, while 38% of patients were 65 or older. Survival benefits can be obtained in both age groups (see [Clinical Trials]). In pancreatic cancer trials, 53% of patients were younger than 65 years of age, while 47% were older than 65 years. No significant safety or pharmacokinetic differences were seen between young or elderly patients. Therefore it is recommended that dose adjustments not be required for elderly patients.

medicine interactions

Erlotinib is metabolized by the liver, mainly through CYP3A4, and a small amount through CYP1A2 and the lung isoenzyme CYP1A1. Any inhibitors or inducers metabolized by these enzymes or enzymes may interact with erlotinib.

CYP3A4 strong inhibitor can reduce erlotinib metabolism and increase its plasma concentration. Compared with erlotinib alone, ketoconazole (200 mg twice daily for 5 days) resulted in increased erlotinib exposure by inhibiting the metabolic activity of CYP3A4 (average erlotinib exposure increased by 86% [AUC]), Cmax 69% increase. When erlotinib was combined with ciprofloxacin, a CYP3A4 and CYP1A2 inhibitor, erlotinib exposure [AUC] and Cmax increased by 39% and 17%, respectively. Therefore, when erlotinib is combined with a strong CYP3A4 inhibitor or in combination with a CYP3A4 / CYP1A2 inhibitor, care should be taken that once a toxic effect is found, the erlotinib dose should be reduced.

CYP3A4 strong inducer can increase the metabolism of erlotinib and significantly reduce the concentration of erlotinib. Compared with erlotinib alone, rifampin (600 mg once daily for 7 days) after administration of 150 mg of erlotinib resulted in a 69% reduction in the average AUC of erlotinib by inducing CYP3A4 metabolic activity.

If rifampin has been used before or during treatment, the average exposure of erlotinib after a single dose of 450 mg [AUC] is 57.5 after a single dose of 150 mg erlotinib without rifampin treatment %. If possible, other medications that are not strongly CYP3A4-inducible should be selected. For patients who need to be treated with erlotinib + strong CYP3A4 inducers (such as rifampicin), the dose should be increased to 300 mg under close monitoring of the drug safety. If it can be well tolerated for more than 2 weeks, consider changing The dose was further increased to 450 mg while closely monitoring drug safety. Higher doses have not been studied under these conditions.

Erlotinib pretreatment or combination had no effect on the clearance of the prototype CYP3A4 substrate midazolam and erythromycin. Therefore, significant interactions with other CYP3A4 substrate clearance are unlikely to occur. Oral availability of midazolam appears to be reduced by 24%, but this is not due to the effect of CYP3A4 activity.

Erlotinib's solubility is related to pH. As the pH increases, the solubility of erlotinib decreases. In combination with erlotinib and the proton pump inhibitor omeprazole, erlotinib exposure [AUC] and maximum concentration [Cmax] were reduced by 46% and 61%, respectively. There was no change in Tmax or half-life. Therefore, drugs that affect the pH of the upper digestive tract may alter the solubility of erlotinib, thereby altering its bioavailability. Increasing the dose of erlotinib when used with these drugs is unlikely to compensate for the reduction in exposure.

Smoking may decrease the plasma concentration of erlotinib, and it is recommended that smokers quit smoking (see [Pharmacokinetics]).

[Drug overdose]

A single oral dose of 1000 mg in healthy subjects and a single oral administration of 1600 mg per week in cancer patients can be tolerated. Healthy subjects were poorly tolerated with a 200 mg dose twice a day for only a few days. According to the data from these trials, unacceptable serious adverse events (such as diarrhea, rash, and elevated liver transaminase) may occur at recommended doses of more than 150 mg per day, see [Dosage and Administration]. When overdose is suspected, erlotinib should be stopped and symptomatic treatment should be given.

Erlotinib clinical trial

The following information comes from foreign clinical studies.

Erlotinib monotherapy for non-small cell lung cancer

A randomized double-blind placebo-controlled trial was performed in patients with locally advanced or metastatic NSCLC who had failed at least one chemotherapy regimen to evaluate the efficacy and safety of erlotinib monotherapy in 731 patients at a 2: 1 ratio. The proportion was randomized to receive erlotinib 150 mg once daily or placebo (488 in the erlotinib group and 243 in the placebo group) until disease progression or unacceptable toxicity. The efficacy indicators of the trial include overall survival, objective response rate, and time to disease-free progression (PFS). The duration of remission is also evaluated. The main efficacy indicator is survival. The trial was conducted in 17 countries and approximately 1/2 patients (326 patients). There are data on EGFR expression.

Table 4 summarizes the general conditions and disease characteristics of the trial population. The general situation of patients in the two treatment groups was very balanced. About two-thirds of the patients are male. About a quarter of patients had a baseline ECOG fitness score (PS) of 2 and 9% of baseline ECOG PS scores of 3. 50% of patients had previously received only one chemotherapy regimen. About 3/4 of the patients had a history of smoking.

Table 4: General conditions and disease characteristics

Erlotinib (N = 488) Placebo (N = 243)

Characteristics n% n%

gender

Female 173 (35) 83 (34)

Male 315 (65) 160 (66)

age)

<65 299 (61) 153 (63)

65 189 (39) 90 (37)

Race

White people 379 (78) 188 (77)

Black 18 (4) 12 (5)

Asian 63 (13) 28 (12)

Others 28 (6) 15 (6)

Baseline ECOG Behavior Status Score *

0 64 (13) 34 (14)

1 256 (52) 132 (54)

2 126 (26) 56 (23)

3 42 (9) 21 (9)

Weight loss before June

<5% 320 (66) 166 (68)

5 10% 96 (20) 36 (15)

> 10% 52 (11) 29 (12)

Unknown 20 (4) 12 (5)

Smoking history

Non-smoking 104 (21) 42 (17)

Smoking or quitting 358 (73) 187 (77)

Unknown 26 (5) 14 (6)

Histological typing

Adenocarcinoma 246 (50) 119 (49)

Squamous cell carcinoma 144 (30) 78 (32)

Undifferentiated large cell carcinoma 41 (8) 23 (9)

Mixed non-small cell carcinoma 11 (2) 2 (<1)

Others 46 (9) 21 (9)

Time to diagnosis of random grouping (month)

<6 63 (13) 34 (14)

6 to 12 157 (32) 85 (35)

> 12 268 (55) 124 (51)

Best response to previous chemotherapy at baseline *

CR / PR 196 (40) 96 (40)

PD 101 (21) 51 (21)

SD 191 (39) 96 (40)

Number of previous chemotherapy regimens at baseline *

1 243 (50) 121 (50)

2 238 (49) 119 (49)

3 7 (1) 3 (1)

Platinum at previous chemotherapy *

Yes 454 (93) 224 (92)

No 34 (7) 19 (8)

* Stratification factor at baseline; distribution slightly different from values reported at randomization.

The test results are shown in Table 5.

Table 5: Efficacy results

Erlotinib placebo hazard ratio (1) 95% confidence interval p-value

Median survival time 6.7 months Median 4.7 months 0.73 0.61 to 0.86 <0.001 (2)

1-year survival rate 31.2% 21.5%

Median progression-free survival 9.9 weeks Median 7.9 weeks 0.59 0.50 to 0.70 <0.001 (2)

Tumor response rate (CR + PR) 8.9% 0.9% <0.001 (3)

Median time to remission 34.3 weeks Median 15.9 weeks

(1) COX regression model analysis using the ECOG behavior status score, the number of previous chemotherapy regimens, the best efficacy of previous chemotherapy containing platinum and the previous chemotherapy as covariates.

(2) Bilateral Log-Rank test stratified by ECOG behavior status score, number of previous chemotherapy regimens, platinum containing previous chemotherapy and best efficacy of previous chemotherapy.

(3) Two-sided Fisher's exact test.

Survival analysis was performed in people with treatment intent. Figure 1 shows the Kaplan-Meier curve for overall survival. The main efficacy indicators of survival and PFS analysis were bilateral Log-Rank tests stratified by the ECOG behavioral status score, the number of previous chemotherapy regimens, the platinum containing the previous chemotherapy, and the best efficacy of the previous chemotherapy.

Figure 1: Kaplan-Meier curve of overall survival for patients in the treatment group

Note: HR was derived from a COX regression model analysis using the ECOG behavioral status score, the number of previous chemotherapy regimens, the platinum-containing prior chemotherapy, and the best effect of previous chemotherapy as covariates. P-values were obtained from a bilateral Log-Rank test stratified by the ECOG behavioral status score, the number of previous chemotherapy regimens, the platinum content of previous chemotherapy, and the best efficacy stratification of previous chemotherapy.

A series of subgroups of patients were studied in an exploratory univariate analysis. Figure 2 shows the results of the analysis. The survival of erlotinib treatment was similar in most subgroups of patients. But the effect was more pronounced in two subgroups: patients with tumor EGFR positive (HR = 0.68) and non-smoker patients (HR = 0.42). These subgroups are discussed further below.

Figure 2: Relative survival hazard ratios of patients in each subgroup by pretreatment characteristics (erlotinib than placebo)

Note: The HR, 95% confidence interval (CI), and sample size (N) for HR in each subgroup of patients receiving erlotinib compared to patients receiving placebo are shown. The vertical mark on the horizontal line represents HR, and the length of the horizontal line represents 95% CI. The left side of the vertically marked vertical line represents an HR less than 1.00, indicating that the erlotinib-treated group has a longer survival compared to the placebo group in this subgroup.

Correlation between the efficacy of erlotinib monotherapy for NSCLC and the expression of EGFR protein (determined by immunohistochemical methods)

The analysis of the relationship between EGFR expression status and treatment effect is limited because the EGFR expression in only 326 patients (45%). EGFR expression was measured in patients with tissue samples before trial enrollment. Nevertheless, the survival of patients tested for EGFR expression and the efficacy of erlotinib monotherapy were almost identical to the results in the overall trial population, suggesting that the EGFR test population is a representative sample. Positive EGFR expression is defined as EGFR staining of at least 10% of cells, while the specific positive value in the EGFR pharmDxTM kit description is 1%. The pharmDx kit has not been validated for non-small cell lung cancer.

Erlotinib monotherapy can prolong the survival of patients with EGFR-positive subgroup (N = 185, HR = 0.68, 95% CI = 0.49 0.94) (Figure 3), and prolong the survival of patients without EGFR subgroup ( N = 405, HR = 0.77, 95% CI = 0.61 0.98) (Figure 5), but had no effect on the survival of patients with EGFR negative subgroup (N = 141, HR = 0.93, 95% CI = 0.63 1.36) (Figure 4). However, the confidence intervals of the EGFR-positive, negative, and untested subgroups are wide and overlap each other, so it cannot be ruled out that erlotinib can also prolong survival in EGFR-negative NSCLC patients.

For non-smoker subgroups, EGFR status also predicts survival benefit for erlotinib. Erlotinib has a more significant effect on prolonging survival in non-smoking and EGFR-positive patients (N = 41, HR = 0.28, 95% CI = 0.13 to 0.61). There are too few patients who do not smoke and are EGFR-negative to conclude.

The remission rate of tumors in all EGFR subgroups was 11.3% in the EGFR positive group, 9.5% in the EGFR unmeasured group, and 3.8% in the EGFR negative group. Progression-free survival was prolonged in patients with EGFR-positive subgroups (HR = 0.49, 95% CI = 0.35 to 0.68), and in patients without EGFR subgroups (HR = 0.60, 95% CI = 0.47-0.75), in EGFR Patients in the negative subgroup were uncertain (HR = 0.80, 95% CI = 0.55 to 1.16).

Figure 3: Survival of EGFR-positive patients

Figure 4: Survival of EGFR-negative patients

Figure 5: Survival of patients without EGFR

Erlotinib combined with chemotherapy for NSCLC

Two multicenter, placebo-controlled, randomized trials involving more than 1,000 patients with locally advanced or metastatic NSCLC in first-line treatment showed results with platinum-based chemotherapy (carboplatin + paclitaxel, erlotinib, N = 526; gemcitabine (+ Cisplatin, erlotinib, N = 580) There was no clinical benefit from taking erlotinib concurrently.

Erlotinib pharmacology and toxicology

Mechanism

The clinical antitumor mechanism of erlotinib has not been fully clarified. Erlotinib inhibits the phosphorylation of intracellular tyrosine kinases associated with epidermal growth factor receptor (EGFR). Whether it has specific inhibitory effects on other tyrosine kinase receptors is not completely clear. EGFR is expressed on the surface of normal cells and tumor cells.

No evidence of potential carcinogenicity was observed in preclinical studies. Erlotinib has neither genotoxicity nor teratogenic effects in genotoxicity studies. Long-term carcinogenicity studies have begun in rats and mice, and precancerous proliferative lesions have not been observed in the 6-month chronic toxicity study.

The genotoxicity of erlotinib was analyzed in a series of in vitro experiments (bacterial mutations, human lymphocyte chromosome aberrations, and mammalian cell mutations) and in vivo mouse bone marrow micronucleus experiments. No genotoxicity was found.

Erlotinib does not affect fertility in female and male rats.

Maternal toxicity can result in embryo / fetal death and miscarriage when rabbit erlotinib plasma drug concentration reaches approximately three times the human plasma concentration (150 mg AUC daily). Plasma drug concentrations administered during organogenesis to approximately human plasma concentrations (according to AUC) do not increase embryo / fetal death and abortion in rabbits and rats. However, female rats receiving erlotinib 30mg / / d to 60mg / / d before mating to the first week of pregnancy (corresponding to 0.3 to 0.7 times the clinical dose based on mg / ) can cause early absorption and Lead to a decline in the number of surviving fetuses.

No teratogenic effects were observed in rabbits and rats.

Erlotinib pharmacokinetics

Data on pharmacokinetic studies in Chinese are lacking. The following information comes from foreign clinical studies.

Erlotinib is absorbed by about 60% after oral administration, and the bioavailability when taken with food significantly increases to almost 100%. The half-life is about 36 hours, which is mainly eliminated by CYP3A4 metabolism, and a small part is metabolized by CYP1A2.

Absorption and distribution

Erlotinib has a bioavailability of approximately 60% at a 150 mg oral dose, and peak plasma concentrations were achieved 4 hours after administration. Food can significantly increase bioavailability to almost 100%.

About 93% of erlotinib binds to albumin and 1 acid glycoprotein (AAG) after absorption. Erlotinib has an apparent volume of distribution of 232 liters.

Metabolism and clearance

Analysis of cytochrome P450 in vitro showed that erlotinib was mainly metabolized by CYP3A4, and a small amount was metabolized by CYP1A2 and extrahepatic isoenzyme CYP1A1. After oral administration of a 100 mg dose, 91% of the drug can be recovered, of which 83% in the stool (1% of the original form) and 8% in the urine (0.3% of the original form).

A pharmacokinetic analysis of 591 people taking a single dose of erlotinib showed a median half-life of 36.2 hours. Therefore, it takes 7 to 8 days to reach steady state plasma concentration. There was no significant correlation between clearance and age. Erlotinib clearance increased by 24% in smokers.

Special population

Patients with abnormal liver function

Erlotinib is cleared mainly in the liver. There are no data on the effect of liver dysfunction or liver metastasis on the pharmacokinetics of erlotinib. (See [Caution]-Patients with abnormal liver function, [Adverse reaction] and [Usage and dosage]-Dose adjustment).

Patients with renal dysfunction

Less than 9% of urine secreted after a single dose. No clinical trials have been performed in patients with renal dysfunction.

interaction

Erlotinib is primarily metabolized by CYP3A4, so it is speculated that inhibitors of CYP3A4 will increase its exposure. When used in combination with ketoconazole, a strong inhibitor of CYP3A4, the AUC of erlotinib increased by 2/3 (see the dose adjustment section in [Drug Interactions] and [Usage and Dosage]).

The use of rifampin, a CYP3A4 inducer, before treatment can increase the clearance of erlotinib by 3 times, and reduce the AUC of erlotinib by 2/3 (see [Drug Interactions] and [Dosage and Administration] Dose adjustment section).

In a phase Ib clinical trial, the pharmacokinetics of gemcitabine and erlotinib did not significantly affect each other.

Erlotinib storage

Store at 25 ° C. It is also acceptable between 15 and 30 ° C.

Keep medicines out of reach of children.

Erlotinib packaging

PVC blister pack

30 tablets / box

Erlotinib validity

36 months

Erlotinib Registration Certificate Number

H20060108

Erlotinib mechanism of action

Erlotinib is different from chemotherapy in that it is a targeted therapeutic drug that can specifically target tumor cells and inhibit tumor formation and growth. It is a small molecule compound that can inhibit the human epidermal growth factor receptor (EGFR) signaling pathway; it is a key component of the epidermal growth factor (also known as HER1) signaling pathway. Both play important roles in growth. Erlotinib inhibits tumor growth by inhibiting the activity of tyrosine kinase, which is one of the important components in EGFR cells.