Summary of lung cancer immunotherapy and precautions

Summary of lung cancer immunotherapy and precautions. The elimination of immune drugs in vivo is not mainly through the liver or kidney, but the main elimination route is through protein catabolism in the reticuloendothelial system or target-mediated disposal.

Chemotherapy is no longer the only option for lung cancer patients. If there is no targeted gene mutation, or the patient has developed resistance to chemotherapy or targeted therapy, and the tumor can no longer be controlled, then immunotherapy becomes a new hope.

We consulted the NCCN Guidelines for Non-Small Cell Lung Cancer (2021.3) and CSCO Guidelines (2020) regarding the treatment recommendations of immunological drugs, as well as the corresponding FDA and NMPA drug instructions, and organized the immunological drug treatments and precautions so that everyone can find them.

Summary:

PD-1: Pembrolizumab (Drug K), Nivolizumab (Drug O)
CTLA-4: Ipilimumab (in combination with O drug)
PD-L1: Atelizumab (T drug), Duvalizumab (I drug)
PD-1
Carrelizumab, tislelizumab, sintilizumab, teriprizumab

Before immunotherapy, it is necessary to improve gland function tests such as cortisol, ACTH, serum growth hormone, reproductive hormone routine, thyroid function, insulin, HA1c, etc.; monitor other organ functions such as heart, lung, skin, etc.; in addition, Need to check hepatitis B, tuberculosis, etc.

Pembrolizumab

Pembrolizumab (Pembrolizumab, Kerida, Keytruda/K drug)
Indications:
NSCLC:
- 1) Single agent for the first-line treatment of locally advanced or metastatic non-small cell lung cancer that is PD-L1 positive and EGFR/ALK negative;
- 2) Combined with pemetrexed and platinum chemotherapy drugs for the first-line treatment of EGFR/ALK-negative metastatic non-squamous non-small cell lung cancer;
- 3) Combine carboplatin and paclitaxel/albumin paclitaxel for the first-line treatment of metastatic squamous non-small cell lung cancer;
- 4) After the progress of platinum chemotherapy

PD-L1 positive

NSCLC.
SCLC: Used for small cell lung cancer that has undergone disease progression after receiving platinum-based chemotherapy and at least one other treatment.
Clinical Trials:
NSCLC:
- 1) KEYNOTE-042 study: PD-L1≧1%, K drug vs chemotherapy, OS prolonged;
- 2) KEYNOTE-189 study (non-squamous): Phase III, K drug + chemotherapy vs chemotherapy, ORR was 48.3%vs19.9%, OS was 22.0vs10.6 months;
- 3) KEYNOTE-407 study (scale): Phase III, K drug + chemotherapy vs chemotherapy, ORR was 62.6%vs38.4%, OS was 17.1vs11.6 months;
- 4) KEYNOTE-010 study: PD-L1 ≥ 1%, K drug versus docetaxel, OS was 11.8 vs 8.4 months.
Non-head-to-head research, which is better and worse is unknown
SCLC: In the KEYNOTE-158 study, the ORR was 18.7%, the PFS was 2.0 months, and the OS was 8.7 months; in the KEYNOTE-028 study, the ORR was 33.3% (n=8/24), the PFS was 1.9 months, and the OS was 9.7 months.
Drug specifications: 100mg/4ml.
Dosage:
- 1) a. 200mg q3w or 400mg q6w; b. The domestic instructions are: 2mg/kg q3w, intravenous infusion for more than 30 minutes, until disease progression or unacceptable toxicity occurs. The infusion time is more than 30 minutes.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose. For grade 4 or grade 3 recurrent adverse reactions, pembrolizumab should be permanently discontinued.
- 3) Special population: There is no need to adjust the dose for renal damage, and no dose adjustment for mild liver damage.
  *If the treatment-related toxicity does not return to grade 0-1 within 12 weeks after the last dose of K drug is given, or the corticosteroid dose cannot be reduced to ≤10 mg prednisone per day or equivalent within 12 weeks, it should be permanently discontinued medicine.

Adverse reactions: fatigue, itching, rash, diarrhea, and nausea. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light, avoid freezing, and avoid shaking. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at room temperature (25°C or below) for up to 8 hours.

Navulumab

Navulumab, Nivolumab (Nivolumab, Odivo, OPDIVO/O drug)
Indications:
NSCLC:
- 1) Nivolumab combined with ipilimumab for the first-line treatment of PD-L1>1% advanced non-small cell lung cancer with negative driver gene;
- 2) nivolimumab + ipilimumab Anti-combined 2-cycle chemotherapy as the first-line treatment for advanced non-small cell lung cancer with negative driver genes.
- 3) Single agent is used to treat locally advanced or metastatic non-small cell lung cancer that is EGFR/ALK negative and has progressed or is intolerable after previous platinum-containing chemotherapy.
SCLC: On December 31, 2020, Drug O withdrew the indication for small cell lung cancer approved in the United States.
Clinical Trials:
NSCLC:
- 1) CheckMate-227 study, for PD-L1 ≥ 1%, O+Y double immunity vs standard chemotherapy, OS is 17.1 months vs 14.9 months;
- 2) CheckMate-9LA: O+Y+2 cycle chemotherapy (design Optimization),;
- 3) CheckMate 017 (squamous cell carcinoma): O drug vs docetaxel, OS is 9.2 vs 6 months; CheckMate-057 (non-squamous cell carcinoma): O drug vs docetaxel, OS is 12.2 vs9 .4 months.
Drug specifications: 40mg/4ml, 100mg/10ml, 240mg/24ml.
Usage and dosage:
- 1) a. O drug 3mg/kg q2w+ ipilimumab 1mg/kg q6w; b. O drug 360mg q3w+ ipilimumab 1mg/kg q6w+ 2 cycles of platinum-containing dual-drug chemotherapy; c. 240mg q2w Or 480mg q4w; b. The domestic instructions are: 3mg/kg or 240mg fixed dose, intravenous injection once every 2 weeks until disease progression or unacceptable toxicity occurs. Intravenous infusion of this product within 30 minutes or 60 minutes.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
  Regarding grade 3/4 recurrent adverse reactions and the persistence of grade 2/3 adverse reactions despite treatment adjustments, nivolumab should be permanently discontinued.
- 3)Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product. 4) Special population: There is no need to adjust the dose for mild to moderate renal damage, and no dose adjustment for mild liver damage.

Adverse reactions: fatigue, itching, rash, diarrhea, and nausea. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at 20～25°C indoor light can be stored for up to 8 hours (8 hours including administration time).

Lpilimumab

Lpilimumab (Ipilimumab, Ipilimumab, Yervoy/Y drug)
Indications:
- 1) Combined with nivolumab (nivolumab) for the first-line treatment of adult patients with PD-L1 -positive and EGFR/ALK-negative metastatic non-small cell lung cancer (NSCLC).
- 2) Combined platinum chemotherapy for adult patients with EGFR/ALK negative metastatic/recurrent non-small cell lung cancer (NSCLC).
Drug specifications: 50mg/10ml, 200mg/40ml
Usage and dosage: 3mg/kg, intravenous infusion is completed within 90 minutes, once every 3 weeks, for 4 consecutive cycles.
Adverse reactions: Common side effects of combined nivolumab are fatigue, rash, itching, diarrhea, musculoskeletal pain, cough, fever, loss of appetite, nausea, abdominal pain, arthralgia, headache, vomiting, dyspnea, dizziness, hypothyroidism and Weight loss. Common side effects of combined nivolumab and chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, loss of appetite, constipation and itching.

Atelizumab

Atezolizumab (Atezolizumab, Tecentriq, Tecentriq/T drug)
Indications:
NSCLC:
- 1) Atelizumab single-agent first-line treatment of EGFR/ALK-negative, PD-L1 high expression (TC≥50% or IC≥10%) metastatic NSCLC patients;
- 2) “Atelizumab +Carboplatin + Albumin Paclitaxel” is used for the first-line treatment of non-squamous cell carcinoma NSCLC patients without EGFR/ALK changes;
- 3) “Atilizumab + Bevacizumab + Carboplatin + Paclitaxel” is used without EGFR /ALK-altered non-squamous cell carcinoma NSCLC patients;
- 4) for NSCLC after platinum chemotherapy has progressed.
SCLC: combined with carboplatin and etoposide for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).
Clinical Trials:
NSCLC:
- 1) IMpower110 study: T drug vs chemotherapy, high PD-L1 expression, OS was 20.2 vs 13.1 months respectively;
- 2) IMpower130 study: T+ chemotherapy vs chemotherapy, OS was 18.6 months vs 13.9 months;
- 3) IMpower150 study, immunity + Chemotherapy + anti-vascular vs chemotherapy + anti-vascular, OS was 19.5 vs 14.7 months, respectively;
- 4) OAK study, T drug vs docetaxel, OS was 13.8 months vs 9.6 months, respectively.
SCLC: IMpower133 study, T drug + EPvs EP, OS were 12.3 months vs. 10.3 months.
Drug specifications: 840mg/14ml, 1200mg/20ml
Dosage:
- 1) NSCLC: a. Single agent, 840mgq2w or 1200mg q3w or 1680mg q4w; b. Combined chemotherapy and/or antivascular therapy, 1200mgq3w, used before chemotherapy and antivascular therapy; after completing 4-6 cycles of chemotherapy, continue T drug 840mg q2w or 1200mg q3w or 1680mg q4w until disease progression or unacceptable toxicity occurs.
  SCLC:
  During the induction period, ativizumab was injected intravenously on day 1, with a recommended dose of 1200 mg, followed by intravenous infusion of carboplatin, and then etoposide.
  Etoposide was given intravenously on day 2 and day 3.
  The regimen is administered every 3 weeks for a total of 4 treatment cycles.
  The induction period is followed by a chemotherapy-free maintenance period, during which 1200 mg of atilizumab is intravenously infused every 3 weeks until disease progression or unacceptable toxicity occurs.
  The infusion time is more than 60 minutes.
- 2)Dose adjustment:Depending on the safety and tolerability of the individual patient, it may be necessary to suspend or discontinue the drug.
  It is not recommended to increase or decrease the dose.
  If a grade 4 immune-related adverse reaction occurs, or the corticosteroid dose cannot be reduced to ≤10 mg prednisone per day or an equivalent dose within 12 weeks after the adverse reaction occurs, the treatment with this product should be permanently stopped.
- 3)medicine interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4)Special groups:There is no need to adjust the dose for mild to moderate renal damage, and no dose adjustment for mild liver damage.

Adverse reactions: fatigue, decreased appetite, nausea, cough, dyspnea, fever, diarrhea, etc. The most common adverse reactions associated with other drug treatments (primarily chemotherapy) are: anemia, neutropenia, alopecia, thrombocytopenia, and constipation. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at 20～25°C indoor light can be stored for up to 8 hours (8 hours including administration time).

Duvalizumab

Duvalizumab (Durvalumab, Infineon, IMFINZI/I drug)
Indications:
- 1) NSCLC: It is suitable for the treatment of unresectable, stage III non-small cell lung cancer (NSCLC) patients who have not progressed after receiving platinum-based chemotherapy and concurrent radiotherapy.
- 2) SCLC: combined with carboplatin/cisplatin and etoposide for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).
Clinical trials:
- 1) NSCLC: PACIFIC study, the OS was 47.5 months, and the 4-year OS rate was 49.6%.
- 2) SCLC: I drug + EP vs EP, OS was 13.0 months vs. 10.3 months.
Drug specifications: 500mg/10ml, 120mg/2.4ml.
Usage and dosage:
- 1) a. Stage III NSCLC: ≥30kg, 10mg/kg q2w or 1500mgq4w; <30kg, 10mg/kg q2w; b. SCLC: ≥30kg, 1500mg q3w combined with chemotherapy, and subsequent single-agent maintenance 1500mg q4w; <30kg , 20mg/kg q3w combined with chemotherapy, followed by a single agent to maintain 10mg q2w. The infusion time is more than 60 minutes.
- 2)Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
- 3) Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4) Special population: There is no need to adjust the dose for mild to moderate renal damage, and no dose adjustment for mild liver damage.
Adverse reactions: Cough, fatigue, pneumonia/radiation pneumonia, upper respiratory tract infection, dyspnea, and rash are common in the treatment of stage III lung cancer; nausea, fatigue/asthenia, and hair loss are common in the treatment of small cell lung cancer. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at room temperature (25°C or below) for a maximum of 4 hours.

Carrelizumab

Carrelizumab (Camrelizumab, Erica)
Indications:The combination of pemetrexed and carboplatin is suitable for unresectable locally advanced or metastatic non-squamous non-small cell lung cancer with negative epidermal growth factor receptor (EGFR) gene mutation and anaplastic lymphoma kinase (ALK) negative ( NSCLC) first-line treatment.
Clinical Trials: CameL study (non-squamous), Carrell beads + Pemezine/Platinum vs Pemezine/Platinum, OS 27.9 vs 20.5 months; SHR-1210-III-307 study (squamous cell carcinoma), Carelellibead + Paclitaxel +Platinum vs. Paclitaxel+Platinum, PFS is prolonged.
Drug specifications: 200mg/bottle
Usage and dosage:
- 1) 200mg/time, intravenously once every 3 weeks, until the disease progresses or intolerable toxicity appears. When karelizumab is administered in combination with chemotherapy, karelizumab should be given intravenously first, and chemotherapy should be given at least 30 minutes later.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
- 3) Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4) Special population: There is no need to adjust the dose for mild liver and kidney damage.
Adverse reactions: Common adverse reactions of combined treatment include reactive capillary hyperplasia (77.6%), anemia, neutropenia, abnormal liver enzymes, thrombocytopenia, nausea, fatigue, decreased appetite, constipation, vomiting, edema, Skin rash, pruritus, hypothyroidism. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at room temperature (25°C or below) for up to 6 hours.

Tilelizumab

Tislelizumab (Tislelizumab, Bezean)
Indications: Combine paclitaxel and carboplatin for the first-line treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC).
Clinical trials:
- 1) RATIONALE307 study (squamous cell carcinoma), tisleli beads + paclitaxel/white violet + platinum vs paclitaxel/white violet + platinum, PFS is 7.6 vs 5.5 months;
- 2) RATIONALE 304 study (non-squamous) , Tilelizhu + Peimex/Platinum vs Peimex/Platinum, PFS is 9.7 vs 7.6 months.
Drug specifications: 100mg/10ml
Usage and dosage:
- 1) The recommended dose is 200mg, administered once every 3 weeks. Use the drug until the disease progresses or intolerable toxicity occurs.
  The first infusion time should be no less than 60 minutes; if well tolerated, the time for each subsequent infusion should be no less than 30 minutes.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
- 3) Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4) Special population: No dose adjustment is required for mild liver damage, and no dose adjustment for mild to moderate renal damage.
Adverse reactions: fatigue, skin rash, hypothyroidism, elevated alanine aminotransferase and aspartate aminotransferase. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 20 hours, and at room temperature (25°C or below) for a maximum of 2 hours.

Sintilimab

Sintilimab (Sintilimab, Daboshu)
Indications: Combination of pemetrexed and platinum-based chemotherapy is used for the first-line treatment of non-squamous non-small cell lung cancer (nsqNSCLC).
Clinical trials:
- 1) ORIENT-11 study (non-squamous), Sindili + Peimerate/Platinum vs. Peimerite/Platinum, PFS was 8.9 vs 5.0 months;
- 2) ORIENT-12 study (squamous cell carcinoma), Sindili +GP vs GP, PFS is 5.5 vs 4.9 months.
Drug specifications: 100mg/10ml
Usage and dosage:
- 1), the recommended dose is 200mg, administered once every 3 weeks. Use the drug until the disease progresses or intolerable toxicity occurs. The infusion time is 30-60 minutes.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
- 3) Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4) Special population: There is no need to adjust the dose for mild liver and kidney damage.
Adverse reactions: fever, anemia, elevated aspartate aminotransferase, elevated alanine aminotransferase, fatigue, decreased white blood cell count. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at room temperature (25°C or below) for up to 6 hours.

Treprizumab

Tislelizumab (Tislelizumab, Tuoyi)
Indications: Indications for lung cancer have not yet been approved
Clinical trial: CHOICE-01 study (squamous/non-squamous), phase III, combined chemotherapy vs chemotherapy, prolonged PFS.
Drug specifications: 240mg/bottle
Usage and dosage:
- 1) 3 mg/kg, intravenous infusion once every 2 weeks until the disease progresses or intolerable toxicity occurs. The first infusion time should not be shorter than 60 minutes; if well tolerated, the subsequent infusion time can be completed within 30 minutes.
- 2) Dosage adjustment: According to the safety and tolerability of individual patients, it may be necessary to suspend or stop the administration. It is not recommended to increase or decrease the dose.
- 3) Drug interactions: Avoid using systemic corticosteroids or immunosuppressants before using this product.
- 4) Special population: There is no need to adjust the dose for mild liver and kidney damage.
Adverse reactions: fatigue, skin rash, hypothyroidism, elevated alanine aminotransferase and aspartate aminotransferase. Pay special attention to immune-related adverse reactions such as immune pneumonia, hepatitis, nephritis, colitis, endocrine diseases, etc.
Drug storage: refrigerate at 2-8°C, avoid light and avoid freezing. If the prepared solution cannot be used immediately, it can be stored at 2～8ºC in the dark for 24 hours, and at room temperature (25°C or below) for up to 8 hours.

Reminding:

The elimination of immune drugs in vivo is not mainly through the liver or kidney, but the main elimination route is through protein catabolism in the reticuloendothelial system or target-mediated disposal.

Drug interactions and whether liver and kidney function damage needs to adjust the dose can be deduced based on the characteristics of immune drug clearance in the body (personal opinion only).

(source:internet, reference only)

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Summary of lung cancer immunotherapy and precautions