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The evolution of advanced non-small cell lung cancer treatment: Is long-term survival possible in the squamous cell patient population?


Alastair Greystoke

Senior Lecturer and Honorary Consultant in Medical Oncology, Newcastle University and the Northern Centre for Cancer Care, Newcastle, UK

Acknowledgements: Bristol-Myers Squibb Pharmaceuticals Limited has had full editorial control over the content of this Insight article. Medical writing assistance was provided by Reynolds-MacKenzie and supported by Bristol-Myers Squibb Pharmaceuticals Limited. Prescribing information has been included at the end of the article. 

Support: This promotional article has been developed and funded by Bristol-Myers Squibb Pharmaceuticals Limited.

10 years ago, long-term survival for advanced non-small cell lung cancer (NSCLC) patients seemed far-fetched, but how are we faring now? Dr Alastair Greystoke, Senior Lecturer and Honorary Consultant in Medical Oncology, from Newcastle University and the Northern Centre for Cancer Care, shares his thoughts on the latest findings in patients with squamous cell NSCLC and his experience in treating the disease. 


Q. What is squamous cell NSCLC?
Squamous cell lung cancer is a histological subtype of the most common type of lung cancer, NSCLC, which accounts for approximately 87% of lung cancers in the UK.1 Amongst the subtypes of NSCLC, squamous cell tends to develop in smokers, rather than non-smokers,2 and accounts for around 30% of cases.3 The cancer most often grows near the centre of the lung,1 and usually presents itself in symptoms such as persistent cough, shortness of breath, haemoptysis (coughing up blood), chest pain, and recurring chest infections.4

A diagnosis of lung cancer currently represents a damning indictment – there are over 46,000 new cases of lung cancer in the UK each year,5 and the number of lung cancer deaths is almost equivalent to prostate, breast and bowel cancer deaths combined.5,6,7,8

Q. How has the squamous NSCLC treatment landscape evolved over the last decade?
The last few years have seen significant advancements in the treatment of squamous cell NSCLC; until 2015, we generally used platinum doublet chemotherapy. When patients progressed, the options for them were docetaxel (not a particularly well-tolerated treatment in this population) or best supportive care – nothing else. The primary aim of treatment before immunotherapy was symptom palliation. Lung cancer symptoms drive quality of life (QoL) in patients, so the goals of treatment were to reduce the effect of cancer-related symptoms and shrink the tumour down. In reality, a large number of patients didn’t respond, and we probably detrimentally impacted their QoL and potentially shortened their life expectancy.

The introduction of immunotherapy changed the treatment landscape in squamous cell NSCLC, and nivolumab ▼ was the first of these treatments.9 Immunotherapy has given us an extra treatment option when chemotherapy has not worked or has stopped working.9,10,11 It is an option that is well tolerated in the majority of cases, gives long lasting disease control in some patients, and has the potential to improve symptoms allowing patients to lead normal lives.9,10,11

Q. What are the current treatment options in advanced second-line squamous cell NSCLC?
The standard of care for second-line squamous cell NSCLC is now immunotherapy. There are a number of immunotherapies that have received Marketing Authorisations for use in the UK for the treatment of this subtype of NSCLC, and immunotherapy is now a mainstay of clinical practice.9,10,11

Performance status is a very important measure when deciding whether or not to prescribe an immunotherapy treatment to patients. If their ECOG performance status is not between 0 and 1, the treatment is not funded through the Cancer Drugs Fund. Clinical trial data into performance status shows that it may be appropriate to give/prescribe immunotherapy to performance status 2 patients (those who are not fit and healthy) unlike chemotherapy, but the benefit for these patients is nowhere near as profound as those who are performance level 0-1.12,13

Sometimes, docetaxel is prescribed to second-line patients who are contra-indicated for immunotherapy (if they suffer with severe active autoimmune disease, if they have brain metastases, or if they require high levels of steroids to keep their performance status up, for example), if they are otherwise performance level 0-1, but this group of patients is relatively rare.9,14

Q. What is the licence of nivolumab in advanced squamous cell NSCLC and what data support its efficacy within this indication?
Nivolumab is licensed as monotherapy for the treatment of locally advanced or metastatic NSCLC after prior chemotherapy in adults.9

The key data that we have in this squamous cell patient population are from the Phase III, CheckMate -017 study which had a primary endpoint of overall survival (OS) and showed a marked improvement in survival rates for nivolumab compared to docetaxel.3 In the study, the number of people alive at one year with nivolumab was 42.0% (95% confidence interval (CI), 34.0 - 50.0) versus 24.0% with docetaxel (95% CI, 17.0 – 31.0)3 with a three month improvement in median OS for nivolumab versus docetaxel (9.2 months (95% CI, 7.3 - 13.3) versus 6.0 months (95% CI, 5.1 - 7.3), respectively).3 The risk of death was 41.0% lower with nivolumab (hazard ratio (HR), 0.59; 95% CI, 0.44 - 0.79; P<0.001).3

In advanced squamous cell NSCLC, programme death-ligand 1 (PD-L1) levels are not significantly associated with the efficacy of nivolumab meaning that it is not a good biomarker in this setting.3

Recent data for nivolumab from the extension phase of CheckMate -017 represent the longest follow-up data we have to date, certainly in the squamous cell patient population.15 After a minimum of three years follow-up, OS rates were 16.0% with nivolumab and 6.0% with docetaxel (HR, 0.62; 95% CI, 0.48 - 0.80).15 What is really nice about the three-year data for CheckMate -017 is that OS seems to be relatively consistent between 15% and 20% of nivolumab patients,15 and that matches results from CheckMate-003 data,16 a different Phase I patient population and a patient population more like what we would see in the real world (though caution must be taken when making cross-trial comparisons). For these patients it is incredibly valuable and a real game-changer over what we had before. We’re also seeing patients in clinical practice deriving this longer-term benefit from nivolumab, meaning that some patients may not need any more systemic treatment for their lung cancer.

Q. What is the safety profile of nivolumab in advanced squamous cell NSCLC?
The most frequent treatment-related adverse events, of any grade, observed in patients treated with nivolumab in the CheckMate -017 study included fatigue (16.7%), nausea (11.0%), decreased appetite (10.8%), asthenia (10.5%), diarrhoea (8.4%).17

In clinical practice, patients do sometimes feel quite fatigued after their first dose of nivolumab treatment,17 this is possibly because they are getting the immune system up and running. After this, treatment normally gets easier rather than harder, which is the opposite situation from chemotherapy where fatigue gets worse over time.18

Q. What is the dosing schedule for nivolumab in advanced squamous cell NSCLC?
Nivolumab is currently administered as an infusion of 240mg intravenously over a period of 30 minutes, every two weeks to treat NSCLC.9 Generally, patients get into a routine of visiting the hospital every two weeks for their nivolumab, and usually find the visits much easier than previous chemotherapy treatments.

Q. What does the future hold for treating squamous cell NSCLC?
In the next one to two years, it is my belief that we will be giving combination treatment routinely – whether immunotherapy plus immunotherapy, or immunotherapy plus chemotherapy – which will be a positive step for the personalisation of immunotherapy treatment.

I would also like to see evolution in the identification and use of robust and accurate biomarkers (this might be tumour mutational burden, or it could be something else) to ensure we can really personalise treatment and choose the most effective form of immunotherapy for each individual patient.



Consult Summary of Product Characteristics (SmPC) prior to prescribing and for full information on the medicinal product. If prescribing OPDIVO in combination with ipilimumab, please also consult the ipilimumab SmPC.

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. PRESENTATION: 10 mg/mL concentrate for solution for infusion. Available in 4 ml (contains 40 mg nivolumab), and 10 ml (contains 100 mg nivolumab) vials. INDICATION: As monotherapy or in combination with ipilimumab for treatment of advanced (unresectable or metastatic) melanoma in adults. Relative to Opdivo monotherapy, an increase in PFS and OS for combination of Opdivo with ipilimumab is established only in patients with low tumour PD-L1 expression. As monotherapy for the adjuvant treatment of adults with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. As monotherapy for treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy, advanced renal cell carcinoma (RCC) after prior therapy, relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin, and squamous cell cancer of the head and neck (SCCHN) in adults progressing on or after platinum-based therapy.

DOSAGE: Opdivo as monotherapy (excluding adjuvant therapy): Recommended dose is Opdivo 240 mg every 2 weeks over 30 minutes intravenously (i.v.). For advanced (unresectable or metastatic) melanoma and RCC only, Opdivo can also be administered at 480 mg every 4 weeks over 60 minutes i.v. (refer to section 4.2 & 5.1 of SmPC). Adjuvant treatment of melanoma: Recommended dose of Opdivo is 3 mg/kg nivolumab administered i.v. over 60 minutes every 2 weeks. For adjuvant therapy, the maximum treatment duration with Opdivo is 12 months. Opdivo in combination with ipilimumab: Melanoma: Recommended dose is 1 mg/kg Opdivo (i.v.) over 30 minutes in combination with 3 mg/kg ipilimumab (i.v.) over 90 minutes every 3 weeks for the first 4 doses, followed by Opdivo monotherapy (i.v.) at either 240 mg every 2 weeks or 480 mg every 4 weeks. For the Opdivo monotherapy phase, the first dose of Opdivo should be administered as follows: 3 weeks after the last dose of the combination phase if using 240mg every 2 weeks or, 6 weeks after the last dose of the combination phase if using 480mg every 4 weeks (refer to section 4.2 of SmPC). Administration: Opdivo is for IV use only. It is to be administered as an IV infusion over a period of 30 or 60 minutes depending on the dose (refer to section 4.2 of SmPC). Total dose of Opdivo required can be infused directly as a 10 mg/mL solution or diluted with sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) solutions for injection. It must not be administered as an intravenous push or bolus injection. When administered in combination with ipilimumab, Opdivo should be given first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion. Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Special populations: Children: Safety and efficacy in children below 18 years of age not established. Elderly: No dose adjustment required. Renal impairment: No dose adjustment required in mild-to-moderate renal impairment. Hepatic impairment: No dose adjustment required in patients with mild hepatic impairment. Caution advised in patients with moderate or severe hepatic impairment.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients listed in SmPC.

WARNINGS AND PRECAUTIONS: Immune-related adverse reactions have occurred at higher frequencies with Opdivo in combination with ipilimumab than with Opdivo monotherapy. Cardiac adverse events and pulmonary embolism have also been reported with combination therapy. Monitor patients for cardiac and pulmonary adverse reactions continuously, plus clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration before and during treatment. Discontinue Opdivo in combination with ipilimumab for lifethreatening or recurrent severe cardiac and pulmonary adverse reactions. Monitor patients continuously (at least up to 5 months after the last dose) as an adverse reaction with Opdivo or Opdivo in combination with ipilimumab may occur at any time during or after discontinuation of therapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications. See SmPC for further information. Immune-related pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, endocrinopathies: Monitor patients for signs and symptoms. Please refer to SmPC for further management guidance including discontinuation of treatment. Immune-related skin adverse reactions: Monitor patients for rash, including Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN). Use caution when considering Opdivo in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents. See SmPC for further information. Other immune-related adverse reactions: Opdivo as monotherapy or in combination with ipilimumab: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis and rhabdomyolysis. Cases of Vogt-Koyanagi Harada syndrome have been reported post-marketing. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, Opdivo or Opdivo in combination with ipilimumab should be withheld or discontinued and appropriate treatment instituted. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with Opdivo may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with Opdivo versus the risk of possible organ rejection should be considered in these patients. Infusion reactions: Severe infusion reactions have been reported. Disease-specific precautions: For patients with poorer prognostic features and/or aggressive disease, where nivolumab should be used with caution after careful consideration of the potential benefit/risk on an individual basis, please consult SmPC section 4.4. cHL - Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT) in cHL. Preliminary results from the follow up of patients undergoing allogeneic HSCT after previous exposure to Opdivo showed a higher than expected number of cases of acute graft-versus-host-disease (aGVHD) and transplant related mortality (TRM). Careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case by case. Treatment with Opdivo may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with Opdivo versus the possible risk should be considered in these patients. Tumour lysis syndrome (TLS) has been observed at an unknown frequency.

Patients on controlled sodium diet: Please refer to SmPC. DRUG INTERACTIONS: Opdivo is not metabolised by drug metabolising enzymes, therefore metabolic drug-drug interactions are not expected. Systemic corticosteroids and other immunosuppressants should be avoided before starting Opdivo; however, systemic corticosteroids and other immunosuppressants can be used after starting Opdivo to treat immune-related adverse reactions.

PREGNANCY AND LACTATION: Opdivo is not recommended during pregnancy and in women of child-bearing potential not using effective contraception unless clinical benefit outweighs potential risk. Effective contraception should be used for at least 5 months following the last dose of Opdivo. It is unknown whether Opdivo is secreted in human milk.

UNDESIRABLE EFFECTS: Opdivo monotherapy: Very Common: neutropaenia, diarrhoea, nausea, rash, pruritus, fatigue, increased AST/ ALT/ ALP/ lipase/ amylase/ creatinine, hypocalcaemia, lymphopaenia, leucopoenia, thrombocytopaenia, anaemia, hypercalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia. Common: upper respiratory tract infection, infusion-related reaction, hypersensitivity, hypothyroidism, hyperthyroidism, hypoglycaemia, decreased appetite, peripheral neuropathy, headache, dizziness, hypertension, pneumonitis, dyspnoea, cough, stomatitis, colitis, vomiting, abdominal pain, constipation, dry mouth, vitiligo, dry skin, erythema, alopecia, musculoskeletal pain, arthralgia, pyrexia, oedema, increased total bilirubin, hypermagnesaemia, hypernatraemia, weight decreased. Opdivo in combination with ipilimumab: Very Common: dyspnoea, hypothyroidism, decreased appetite, headache, colitis, diarrhoea, vomiting, nausea, abdominal pain, rash, pruritus, arthralgia, fatigue, pyrexia, increased AST/ ALT/ total bilirubin/ ALP/ lipase/ amylase/ creatinine, lymphopaenia, leucopoenia, neutropenia, thrombocytopaenia, anaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, hypoglycaemia. Common: pneumonia, upper respiratory tract infection, eosinophilia, infusion-related reaction, hypersensitivity, adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis, dehydration, hepatitis, peripheral neuropathy, dizziness, uveitis, blurred vision, tachycardia, hypertension, pneumonitis, pulmonary embolism, cough, stomatitis, pancreatitis, constipation, dry mouth, vitiligo, dry skin, erythema, alopecia, urticaria, musculoskeletal pain, renal failure, oedema, pain, hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased. Please refer to SmPC for full list of adverse reactions.

40 mg / 4mL 1 vial (EU/1/15/1014/001) £439.00;
100 mg / 10mL 1 vial (EU/1/15/1014/002) £1,097.00
LOCAL REPRESENTATIVE IN UK:Bristol-Myers Squibb Pharmaceuticals Ltd, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. Tel: 44 0800-731-1736.
LOCAL REPRESENTATIVE IN IRELAND:Bristol-Myers Squibb Pharmaceuticals, Plaza 254, Blanchardstown Corporate Park 2, Ballycoolin, Dublin 15, Tel: 353 1 483 3625.

Adverse events should be reported. Reporting forms and information can be found at:
UK - www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store;
Ireland - Freepost HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: 353 1 6764971; Fax: 353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Adverse events should also be reported to Bristol-Myers Squibb via medical.information@bms.com or 0800 731 1736 (UK); 1 800 749 749 (Ireland).


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3 Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015. Epub ahead of print at nejm.org, May 31, 2015. doi: 10.1056/NEJMoa1504627
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10 Pembrolizumab. Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/2498/smpc Last accessed: 06 December 2018
11 Atezolizumab. Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/8442 Last accessed: 06 December 2018
12 Popat, S. et al. Nivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status. Data presentation at European Society for Medical Oncology 2017. Abstract #1303PD
13 Spigel, D.R. et al. CheckMate 153: Randomized Results of Continuous vs 1-Year Fixed-Duration Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer. Data presentation at European Society for Medical Oncology 2017. Abstract #1297O
14 Docetaxel. Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/5762/ Last accessed: 03 December 2018
15 Font, E Felip et al. Three-year follow-up from CheckMate 017/057: Nivolumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC). Data presentation at European Society for Medical Oncology 2017. Abstract #1301PD
16 Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab (anti-PD-1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2015 April 20 (Epub ahead of print).
17 Barlesi et al. Long-term Outcomes With Nivolumab vs Docetaxel in Patients With Advanced NSCLC: CheckMate 017 and CheckMate 057 2-y Update. Presented at the ESMO Annual Conference 2017.
18 MacMillan Cancer Support. What causes fatigue? Available at: https://www.macmillan.org.uk/information-and-support/coping/side-effects-and-symptoms/tiredness/what-causes-fatigue.html#6394 Last accessed: 06 December 2018

Job number: 1506UK1801291-03

Date of preparation: December 2018



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