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Table of Contents
PROFESSIONAL RESOURCE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 139-162

Immunotherapy protocols in lung cancer


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication17-May-2019

Correspondence Address:
Sharada Mailankody
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_18_18

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  Abstract 


Immunotherapy has emerged as a valuable treatment option in many advanced malignancies (especially lung cancer). The PD-1 inhibitors (nivolumab and pembrolizumab) and the PD-L1 inhibitors (durvalumab and atezolizumab) have been approved for use in various cancers, alone or in combination with chemotherapy. The protocols for the PD-1/PD-L 1 blockers are listed below. The various indications for these PD-1/PD-L1 blockers, baseline evaluation, monitoring during therapy, and guidelines for the management of immune-related adverse events are described below.

Keywords: Immunotherapy, lung, PD-1/PD l-1 inhibitors


How to cite this article:
Menon N, Mailankody S. Immunotherapy protocols in lung cancer. Cancer Res Stat Treat 2018;1:139-62

How to cite this URL:
Menon N, Mailankody S. Immunotherapy protocols in lung cancer. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Aug 24];1:139-62. Available from: http://www.crstonline.com/text.asp?2018/1/2/139/258536




  Table of Contents Top





  Durvalumab Protocol Top


Name Age Sex: M/F

Diagnosis Stage

Intent: Adjuvant (after concurrent chemoradiotherapy)

Indication: Unresectable Stage III nonsmall cell lung cancer which has not progressed following concurrent platinum-based chemotherapy and radiation therapy, ideally within 42 days of chemoradiotherapy

Frequency: 2 weekly

Duration of treatment: For 12 months or until disease progression or unacceptable toxicity



Premedication: Patients who have experienced Grade 1 or Grade 2 infusion reactions should receive premedication with subsequent doses



Adverse effects

  1. Infusion reactions [1]
  2. Immune-related adverse events [1]


    1. Immune-mediated pneumonitis
    2. Immune-mediated hepatitis
    3. Immune-mediated colitis
    4. Immune-mediated endocrinopathies
    5. Immune-mediated nephritis.


  3. Embryo-fetal toxicity.[1]


Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman.

The incidence of various adverse effects of durvalumab and guidelines for their management are listed in [Table 1] and [Table 2] respectively.
Table 1: Adverse events with durvalumab

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Table 2: Recommended treatment modifications for durvalumab[1]

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  References Top


  1. IMFINZi (Durvalumab) injection PRESCRIBING INFORMATION. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf. [Last accessed on 2019 Apr 12].
  2. Antonia SJ. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. Reply. N Engl J Med 2019;380:990.



  Nivolumab Single Agent Top


Name Registration number Age Sex

Height Weight BSA

Diagnosis

Site Stage

Intent: Palliative

Dose and frequency: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity [1],[2]

Alternative dosages: 240 mg intravenous (IV) every 2 weeks [3] or 480 mg IV every 4 weeks [4]

Comorbidities: Diabetes mellitus/ hypertension/ hypothyroidism/ any others

History of autoimmune disorders

History of steroid intake

History of antibiotic intake in the last 2 weeks

Consent Y/N

Investigations before each cycle: CBC/RFT/LFT/SE/S Ca/S Mg/S PO4

Baseline investigations to be done to monitor for immune-related adverse events (iRAEs)

At baseline and every three cycles

  • TFT
  • ACTH/Serum cortisol (8 AM)
  • Serum FSH/LH
  • Estradiol/testosterone
  • Fasting lipid profile
  • Urine routine examination
  • 2D Echocardiogram (at baseline and whenever clinically indicated).




Premedication: Patients who have experienced Grade 1 or Grade 2 infusion reactions should receive premedication with subsequent doses

  • Any delay Y/N
  • Any iRAE – Y/N
  • If yes, grade of event (NCI CTCAE v4) – 1/2/3/4
  • Other expert opinion taken – Y/N
  • Dose of steroid given
  • Duration of steroids.


The incidence of various adverse reactions and laboratory abnormalities seen with nivolumab are described in [Table 3] and [Table 4] respectively.
Table 3: Adverse reactions occurring in >10% of treated patients and higher incidence than in the chemotherapy arm (CheckMate-037)6 : A phase III trial comparing nivolumab to chemotherapy (dacarbazine or paclitaxel + carboplatin) in patients with melanoma, who had progressed after ipilimumab or ipilimumab and a BRAF-inhibitor, if they were BRAFv100 mutation positive

Click here to view
Table 4: Laboratory abnormalities worsening from the baseline occurring in>10% of patients given nivolumab and at a higher incidence than in the chemotherapy arm (CheckMate 037) : A phase III trial comparing nivolumab to chemotherapy (dacarbazine or paclitaxel + carboplatin) in patients with melanoma, who had progressed after ipilimumab or ipilimumab and a BRAF-inhibitor, if they were BRAFv100 mutation positive

Click here to view


Recommended dose modifications for adverse reactions with nivolumab are listed in [Table 5].
Table 5: Recommended dose modifications for adverse reactions

Click here to view



  References Top


  1. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
  2. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.
  3. Zhao X, Suryawanshi S, Hruska M, Feng Y, Wang X, Shen J, et al. Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol 2017;28:2002-8.
  4. Long GV, Tykodi SS, Schneider JG, Garbe C, Gravis G, Rashford M, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol 2018;29:2208-13.
  5. OPDIVO (Nivolumab) Injection. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s055lbl.pdf. [Last accessed on 2019 Apr 12].
  6. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-84.



  Atezolizumab Single Agent Top


Name Registration number: Age: Sex:

Diagnosis

Site

Stage

Intent: Palliative

Frequency: 3-weekly

Comorbidities: Diabetes mellitus/ hypertension/ hypothyroidism/ any other

History of autoimmune disorders

History of steroid intake

History of antibiotic intake in the last 2 weeks

Consent Y/N

Height

Weight

BSA

Investigations before each cycle:

CBC/RFT/LFT/SE/S Ca/S Mg/S PO4

Baseline investigations to be done to monitor for immune-related adverse events (iRAEs)

At baseline and every 3 cycles

  • TFT
  • ACTH/Serum cortisol (fasting)
  • Serum FSH/LH
  • Estradiol/Testosterone
  • Fasting lipid profile
  • Urine routine examination
  • 2D Echocardiogram (at baseline and whenever clinically indicated).






Any delay in subsequent doses - Y/N

Any iRAE – Y/N

If yes, grade of event (NCI CTCAE v4) – 1/2/3/4

Other expert opinion taken – Y/N

Dose of steroid given

Duration of steroids

The incidence of adverse reactions (clinical and laboratory) due to Atezolizumab have been listed in [Table 6] and [Table 7]. Recommendations for dose modification have been described in [Table 8].
Table 6: Adverse reactions occurring in >10% of patients receiving atezolizumab compared with docetaxel

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Table 7: Laboratory abnormalities occurring in >20% of patients receiving Atezolizumab

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Table 8: Recommended dose modification for adverse reactions with atezolizumab

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  References Top


  1. TECENTRIQ (atezolizumab) Injection. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s010lbl.pdf. [Last accessed on 2019 Apr 12].
  2. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.



  Pembrolizumab Top


Name Age Sex: M/F

Diagnosis

Intent

Frequency: 3-weekly





Premedication

  • No premedication required routinely and for grade1 infusion reactions
  • If a grade 2 infusion reaction occurs, then use premedication for subsequent doses
  • If grade 3 or grade 4 infusion reactions occur, permanently discontinue
  • Paracetamol, diphenhydramine.


Adverse effects of pembrolizumab

  1. Infusion reactions [1]
  2. Immune-related adverse events (iRAEs)[1]


    1. Immune-mediated pneumonitis
    2. Immune-mediated hepatitis
    3. Immune-mediated colitis
    4. Immune-mediated endocrinopathies
    5. Immune-mediated nephritis
    6. Immune-mediated skin disorders – rashes, Stevens–Johnson Syndrome, toxic epidermal necrolysis
    7. Other irAEs include arthritis, uveitis, myositis, Guillain–Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis.


  3. Embryo-fetal toxicity.[1]


Refer to [Table 9] for the incidence of adverse effects of pembrolizumab.
Table 9: Adverse effects of pembrolizumab

Click here to view


Guidelines for dose modification and management for pembrolizumab related adverse events are described in [Table 10] and [Table 11].
Table 10: Dose modification guidelines for pembrolizumab-related adverse events

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Table 11: Pembrolizumab infusion reaction dose modification and treatment guidelines

Click here to view



  References Top


  1. Keytruda PRESCRIBING INFORMATION. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf. [Last accessed on 2019 Apr 12]
  2. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.



  Pemetrexed + Carboplatin + Pembrolizumab Top


Name Age Sex: M/F

Height (cm) Weight (kg) BSA (m2)

Diagnosis Stage

Frequency: 3-weekly

Intent: Palliative



Oral medications

  1. Tablet folic acid 5 mg OD 1 week before then daily until 3 weeks postchemotherapy
  2. Tablet dexamethasone 4 mg BD day 0–2
  3. Capsule aprepitant 125 mg PO on day 1, then 80 mg PO OD on day 2 and day 3
  4. Tablet ranitidine 150 mg BD day 0–2.


*Pembrolizumab should be given before chemotherapy [1]

**CrCl must be ≥45mL/min before the administration of chemotherapy

#Carboplatin: AUC 5 (using Calvert formula). Carboplatin dose not to exceed 750mg. The estimated glomerular filtration rate (GFR) used in the Calvert formula should not exceed 125 ml/min

Drug interactions

  1. Pemetrexed [3]


    • Ibuprofen and NSAIDs with short half-lives (e.g. diclofenac, indomethacin, ketoprofen, and ketorolac) decreases the clearance of pemetrexed leading to increased pemetrexed levels
    • Avoid use or use alternative, discontinue 5 days before, during and 2 days after administration of pemetrexed
    • Aspirin in low-to-moderate doses (325 mg q6h) does not affect the pharmacokinetics of pemetrexed
    • Deferiprone increases toxicity of others by pharmacodynamic synergism. Avoid use of deferiprone, if alternative not possible monitor neutrophil counts more closely
    • Substances secreted by the renal tubules (e.g., probenecid) may increase drug levels by decreasing clearance.


  2. Carboplatin [4]


    • Aminoglycoside antibiotics increased risk of nephrotoxicity and ototoxicity
    • Clozapine increased risk of agranulocytosis, avoid concomitant use
    • Diuretics increased risk of nephrotoxicity and ototoxicity
    • Nephrotoxic drugs increased nephrotoxicity; not recommended
    • Phenytoin reduced absorption of the antiepileptic.


Anti-emetics

  • Highly emetogenic.


Extravasation

  • Nonvesicants.


Toxicity

Hematological and non hematological toxicity (all grades) with pemetrexed +carboplatin are listed in [Table 12].
Table 12: Toxicity with pemetrexed + carboplatin

Click here to view


Dose reduction or discontinuation of chemotherapy may be necessary in certain circumstances (refer to [Table 13]).
Table 13: Dose reduction/discontinuation recommendations

Click here to view


Hepatic impairment

  • No dose adjustments indicated. Pemetrexed is primarily renally excreted unchanged
  • However, it has not been studied in patients with hepatic impairment.


Prevention of pemetrexed-induced toxicity

  • Skin rash has been reported in patients not pre-treated with a corticosteroid
  • Standard therapy to reduce the incidence and severity of skin reactions includes dexamethasone 4 mg PO twice daily given the day before, the day of, and the day after pemetrexed administration [2]
  • Treatment-related toxicity, including bone marrow suppression, diarrhea, and mucositis, are significantly reduced by supplementing with folic acid and Vitamin B12
  • Patients should take 0.4 mg oral folic acid (0.35–1 mg) daily beginning 1 week before and continuing daily until 3 weeks after the last pemetrexed dose
  • At least 5 daily doses must be taken during the 7 days before the start of therapy
  • Patients should also receive Vitamin B12 1000 mcg IM injection 1 week before pemetrexed therapy. This should be repeated every 9 weeks until 3 weeks after the last pemetrexed dose.


Adverse effects of pembrolizumab

Please refer to [Table 9] on page 149.[6]

Dose modification guidelines for pembrolizumab-related adverse event

Please refer to [Table 10] on page 149.[6]

Pembrolizumab infusion reaction dose modification and treatment guidelines

Please refer to [Table 11] on page 150.[1],[6]]


  References Top


  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-92.
  2. Zhang L, Ou W, Liu Q, Li N, Liu L, Wang S, et al. Pemetrexed plus carboplatin as adjuvant chemotherapy in patients with curative resected non-squamous non-small cell lung cancer. Thorac Cancer 2014;5:50-6.
  3. ALIMTA (pemetrexed disodium) Injection. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf. [Last accessed on 2019 Apr 12].
  4. PARAPLATIN Label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020452s005lbl.pdf. [Last accessed on 2019 Apr 12].
  5. Lung Pathway Group – Pemetrexed in Non-Small Cell Lung Cancer (NSCLC). Available from: http://www.rmpartners.cancervanguard.nhs.uk/wp-content/uploads/2017/03/lca-lung-protocol-pemetrexed-1.pdf. [Last accessed on 2018 Dec 24].
  6. Keytruda PRESCRIBING INFORMATION. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf. [Last accessed on 2019 Apr 12].



  Atezolizumab Paclitaxel Carboplatin Bevacizumab Top


Name Regn number Age Sex

Diagnosis

Site

Stage

Intent: Palliative

Frequency: 3 weekly

Comorbidities: Diabetes mellitus/ Hypothyroidism/ Hypertension/ Any others.

If Hypertension present: Well controlled Y/N

History of recent surgery

History of recent bleeding

History of autoimmune disorders

History of steroid intake

History of antibiotic intake in the last 2 weeks

Consent Y/N

Height

Weight

BSA

BP

Investigations before each cycle: CBC/RFT/LFT/SE/S Ca/S Mg/S PO4/Urine routine examination

Baseline investigations to be done to monitor for immune-related adverse events (iRAEs)

At baseline and every three cycles

  • TFT
  • ACTH/Serum cortisol (fasting)
  • Serum FSH/LH
  • Estradiol/testosterone
  • Fasting lipid profile
  • 2D Echocardiogram (at baseline and whenever clinically indicated).


Premedications for paclitaxel

  1. Dexamethasone 20 mg PO 12 and 6 hours before paclitaxel (or per standard of care at treating institution)
  2. Diphenhydramine (or equivalent) 50 mg IV 30–60 minutes before paclitaxel
  3. Cimetidine or ranitidine (or equivalent) 300 mg (or 50 mg) IV (or equivalent) 30–60 minutes before paclitaxel
  4. Capsule aprepitant 125 mg day 1, 80 mg day 2 and day 3
  5. Injection palonosetron 0.25 m IV bolus day 1
  6. Tablet dexamethasone 4mg BD day 2–4.


Order of infusion: Atezolizumab – Bevacizumab – Paclitaxel – Carboplatin [1]

  • njection atezolizumab 1200 mg IV in 250 ml NS over 60 mins (for the first infusion) and then over 30 min for subsequent infusions if tolerated (to use a non-DHEP IV set)
  • Injection bevacizumab 15 mg/kg IV in 100 ml NS over 90 min (for the first infusion) and then over 60 min in the subsequent infusions if tolerated
  • Injection paclitaxel 200mg/m2 IV in 500 ml NS over 3 h in non-DHEP containing IV set (to be given 60 min after the completion of bevacizumab)
  • Injection carboplatin AUC 6 IV in 500ml NS over 30 min (to be given 30 min after completion of paclitaxel).


(Needles or IV administration sets that contain aluminum should not be used in the preparation or administration of carboplatin; aluminum can react with carboplatin resulting in precipitate formation and loss of potency.)

Calvert's formula (target dose in mg = [target AUC] × [GFR + 25])

Dose modification guidelines

- Bevacizumab: refer to [Table 14]
Table 14: Dose modification guidelines for bevacizumab

Click here to view


-Paclitaxel +carboplatin refer to [Table 15], [Table 16], [Table 17], [Table 18]
Table 15: Dose modification for Paclitaxel and Carboplatin

Click here to view
Table 16: Dose modification based on nadir platelet count

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Table 17: Dose modification for Paclitaxel based on hepatic toxicity

Click here to view
Table 18: Dose modification for Paclitaxel based on neurological toxicity

Click here to view


Dose modifications for atezolizumab

Please refer to [Table 8] on page 147.


  Reference Top


  1. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288-301.



  Baseline Assessment Before Starting Immunotherapy Top





  Monitoring during Immunotherapy and Evaluation for Abnormal Findings Top


  • Clinical examination at each visit with adverse event symptom assessment
  • CBC and metabolic panel –repeat every 2-3 weeks during immunotherapy, then in 6-12 weeks or as indicated
  • Thyroid function tests (TSH, free T4) every 4-6 weeks during immunotherapy then follow up every 12 weeks as indicated. Total T3 levels if abnormal thyroid function suspected. Thyroid peroxidase (TPO) antibodies if TSH is high, TSH receptor antibodies (TRAbs) if TSH is low
  • Serum Cortisol every 2-3 weeks during immunotherapy then follow up every 6- 12 weeks. LH, FSH, ACTH and serum testosterone, if hypophysitis/hypopituitarism suspected
  • Routine monitoring for pancreatitis is not indicated in asymptomatic patients. In patients with suspected pancreatitis, serum amylase, lipase, and abdominal imaging should be considered
  • Monitor oxygen saturation based on symptoms. If pneumonitis suspected, perform chest CT, biopsy if needed to exclude other causes
  • Conduct/repeat dermatological examination based on symptoms. If skin lesions appear, monitor affected skin area and lesion type; photographic documentation and biopsy if indicated.



  Immune-Related Adverse Events - Principles of Management Top


  • Corticosteroids are the mainstay of treatment of most irAE-related to immunotherapy
  • Early intervention with corticosteroids is the key goal in the management of immune-related toxicity
  • Use of corticosteroids for irAE has not been shown to reduce anti-tumor efficacy
  • In the absence of specific indications such as prior infusion reaction or concurrent chemotherapy, routine premedication with corticosteroids is not recommended given the potential mitigation of immunotherapeutic effectiveness in the prophylactic setting
  • For neurologic, cardiac, or grade 3 or 4 irAEs, higher dose steroids (e.g., methylprednisolone or prednisone 1–2mg/kg/day) should be given
  • Longer steroid tapers (>4 weeks, sometimes 6-8 weeks or longer) may be required to prevent recurrent irAEs, particularly pneumonitis and hepatitis
  • Higher potency corticosteroids are preferred for short term use for immune-related dermatitis, compared to longer-term use of low potency steroids.



  Prophylactic Medications for Patients on Corticosteroids for Immune-Related Adverse Events Top


  • For patient receiving a prednisone equivalent of 20 mg or more daily for 4 weeks or more, prophylaxis against Pneumocystis Jerovecii pneumonia can be considered
  • For patient receiving a prednisone equivalent of 20 mg or more daily for 6–8 weeks or more, prophylaxis against fungal infections can be considered
  • Prophylaxis against herpes zoster reactivation can be considered
  • Proton pump inhibitors or H2 blockers can be considered for patients at high risk for gastritis.


Special considerations

Fertility

The effect of immunotherapy on human reproductive function is unknown. Consider fertility preservation and reproductive endocrinology referral for all patients starting therapy who have not yet completed their family.

Pregnancy

Patients of reproductive age should be advised to use effective birth control during and for at least 5 months after the final dose of immunotherapy.

Breastfeeding

Breastfeeding is contraindicated during and for at least 5 months after the final dose of immunotherapy.


  Reference Top


  1. Management of Immune Checkpoint Inhibitor-Related Toxicities. NCCN Guidelines Version 1; 2019.



  Indications for Immunotherapy (This List is a General Guideline and is Updated at the Time of Publication, However, There are Multiple Ongoing Immunotherapy Trials, and the Reader is Encouraged to Check the Latest Literature) Top


Durvalumab

  1. Nonsmall cell lung cancer, unresectable: Treatment of unresectable Stage III non-small cell lung cancer which has not progressed following concurrent platinum-based chemotherapy and radiation therapy [2]
  2. Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[1]


Nivolumab

  1. Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient; single agent)
  2. Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient; combination therapy)[3]
  3. Head and neck cancer, squamous cell, recurrent or metastatic [4]
  4. Hepatocellular carcinoma [5]
  5. Hodgkin lymphoma, classical [6]
  6. Melanoma, adjuvant treatment [7]
  7. Melanoma, unresectable or metastatic [8]
  8. Non-small cell lung cancer, metastatic, progressive [9],[10],[11]
  9. Renal cell cancer, advanced (previously treated)[12]
  10. Small cell lung cancer, metastatic [13]
  11. Urothelial carcinoma (locally advanced or metastatic).[14]


Pembrolizumab

  1. Cervical cancer (recurrent or metastatic)[15]
  2. Gastric cancer (recurrent locally advanced or metastatic [16]
  3. Head and neck cancer, squamous cell, (recurrent or metastatic)[17]
  4. Hepatocellular carcinoma (advanced)[18]
  5. Hodgkin's lymphoma, classical (relapsed or refractory)[19]
  6. Melanoma (unresectable or metastatic)[20]
  7. Melanoma, Stage III adjuvant treatment [21]
  8. Merkel cell carcinoma, advanced [22]
  9. Microsatellite instability-high cancer
  10. Nonsmall cell lung cancer (metastatic), single-agent therapy [23]
  11. Nonsmall cell lung cancer (metastatic, nonsquamous), combination therapy [24]
  12. Urothelial carcinoma (locally advanced or metastatic [25]
  13. Primary mediastinal large B-cell lymphoma (relapsed or refractory)[26]
  14. Nonsmall cell lung cancer (metastatic, squamous), combination therapy.[27]


Atezolizumab

  1. Locally advanced or metastatic urothelial carcinoma [28]
  2. Metastatic nonsmall cell lung cancer – single agent [29]
  3. Metastatic nonsmall cell (nonsquamous) lung cancer – in combination with chemotherapy [30]
  4. Extensive stage small cell lung cancer in combination with chemotherapy.(31)



  References Top


  1. Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3:e172411.
  2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919-29.
  3. Overman MJ, Lonardi S, Wong KY, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/Microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-9.
  4. Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.
  5. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-502.
  6. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016;17:1283-94.
  7. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824-35.
  8. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-84.
  9. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.
  10. Vokes E, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ, et al. Nivolumab versus Docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 2018;29:959-65.
  11. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
  12. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
  13. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95.
  14. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18:312-22.
  15. Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE- 158 study. J Clin Oncol 2019;37:1-9.
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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.





 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16], [Table 17], [Table 18]



 

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Durvalumab Protocol
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Nivolumab Single...
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Atezolizumab Sin...
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Pembrolizumab
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Pemetrexed +...
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