Advanced NSCLC

Written by Dr Ahmed Al Badi and Dr Brian Healey Bird

Introduction – Advanced NSCLC

Lung cancer is the commonest cancer diagnosis in both sexes. Half of these diagnoses are locally advanced or associated with distant metastasis. (2) Immunotherapy is now the first line treatment of choice for stage IV Non-Small Cell Lung Cancer (NSCLC) without driver mutations. (3) This article will review these agents combined with chemotherapy or as single agents, and the associated immune related autoimmune side effects (irAE) We will also explore treatment options following immunotherapy, including novel agents targeting KRAS G12C mutations. 2 cases will be used to illustrate these learning points.

Immunotherapy

Immunotherapy capitalises on the body’s ability to recognize self and non self and destroy non self. Tumour cells escape immune surveillance by upregulation of programmed cell death ligand 1(PD-L1) expression which causes exhaustion of effector T cells when they attempt to attack the cancer cell. (4) Testing for PD-L1 tumour proportion score (TPS Tumour cells positive for PD-L1/ viable tumour cells*100%) is now one of the pillars of the initial treatment of NSCLC. Immune checkpoint inhibitors (ICI) such as Pembrolizumab disrupt PDL1 signalling and activate the immune system to attack the cancer in a substantial minority of patients.

The KEYNOTE-024 trial compared the use of first line pembrolizumab to platinum based chemotherapy in advanced NSCLC with PD-L1 >50% and no driver mutations; the group that received pembrolizumab showed a significant overall survival (OS) and longer progression free survival (PFS). (5) In Ireland first line monotherapy with ICI is limited to frail patients who would not tolerate chemotherapy and who have a TPS score >50%. In the USA based on KEYNOTE-042 lung cancer with any PD-L1 score can receive single agent immunotherapy as they accept inferior response rates and financial toxicity more readily. TPS is an imperfect biomarker.

The KEYNOTE-189 trial randomized a patient population of non-squamous NSCLC to either a chemoimmunotherapy group (cisplatin or carboplatin plus pemetrexed combined with pembrolizumab) compared to a placebo. This was followed by pembrolizumab maintenance therapy or placebo. The chemoimmunotherapy arms had increased OS with all subgroups of TPS as demonstrated below. Similar results were demonstrated in the KENOTE-407 trials with squamous cell carcinoma NSCLC (Carboplatin and Paclitaxel ± pembrolizumab or placebo). In Ireland Pembrolizumab, Nivolumab and Atezolizumab are all funded for second line treatment of NSCLC post chemotherapy alone.

Immune Related Autoimmune Side Effects

CTLA-4 is an immune checkpoint found in naïve T cells being exposed to antigen by antigen presenting cells early in T cell maturation. Their use leads to rapid expansion of T cell clones some of which may recognize self-antigen causing autoimmune disease. PD-L1 inhibitors tend to have a lower risk of irAE thanCTLA-4 inhibitors as the T cells have already been through selection in the lymph node and are quiescent but unleashed to attack the cancer cells. In moderate to severe cases treatment cessation and steroids yield good responses. Differential diagnoses including sepsis, thrombosis and chemotherapy side effects need to be considered especially in patient with other comorbidities and polypharmacy.

Rashes and pruritis are common and tend to effect about 40% of patients. These occur early in treatment at the 2-3 week mark and in most cases can be observed and symptomatically managed. Interestingly Vitiligo rashes are usually associated with a good response to immunotherapy. Blistering rashes need a broader differential and other causes investigated. Diarrhoea and colitis can happen in 1.8% of patients at around 6-7 weeks.

Bowel rest and hydration can be sufficient but in moderate to severe disease steroids and hospitalization is warranted. 0.5-1mg/kg of prednisolone with 4-6 week taper to avoid early relapse is recommended. Consider infectious pathogens and a CT scan early. If the diagnosis is uncertain a colonoscopy may be useful. In unresponsive cases a switch to infliximab within 72 hours may be considered. (14)

Hepatitis occurs in about 10% of patients, usually after 8-12 weeks from initiation. This is usually a rise in liver function tests (LFTs) but can manifest as a fever. Consider alternative diagnoses such as thromboembolic events, alcoholic or viral hepatitis and metastatic disease as causes for liver function derangement. A CT scan and hepatitis panel can aid this differential. Normalisation of LFTs can be aided with 0.5mg-1mg of Prednisolone as a 3-week taper. Treatment can be recommenced for mild to moderate hepatitis secondary to immunotherapy after recovery of liver function tests (which may take up to 8 weeks) but should be discontinued in severe hepatitis. (14)

Thyroid dysfunction can happen quite early at 42 days in 6.6% of patients. Usually, presentation is mild symptoms of hypothyroidism but can initially be preceded by hyperthyroid symptoms. This is because it is commonly associated with thyroid autoantibodies and progresses like a thyroiditis. Symptomatic therapy with Levothyroxine for hypothyroidism or non-selective beta blockers for the temporary hyperthyroidism may be beneficial. These patients may recover with time. Other endocrine dysfunction is extremely rare but one emergency to look out for would be adrenal insufficiency in 0.7% of patients who may present with non-specific symptoms or in an adrenal crisis. The latter need hospitalization, aggressive fluid resuscitation and stress dose steroids. (14) Patients whose immune system attacks pancreatic islet cells may present with Diabetic Keto Acidosis.

Pneumonitis can occur in 5% of patients. Patients can present with shortness of breath, coughing, or reduced exercise tolerance. It is a potentially fatal complication. CT is imaging of choice and can show bilateral ground glass opacities. Prednisolone at 1-2mg/kg with a long taper over 4-6 weeks to avoid relapse can help reduce inflammation. Consider infectious causes and a bronchoscopy to out rule these especially in moderate to severe disease or in poor response. (14)

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