[HKU Medical Grand Rounds] Angels and demons: Immunotherapy for treatment of metastatic non-small-cell lung cancer

Introduction

Immunotherapy is gaining increasing attention in Oncology. It works by stimulating or modulating the immune system to fight malignant tumours.¹ While immunotherapy can achieve favourable response in many cancers,² it also carries the risk of severe, or even life-threatening, immune-related adverse events (IRAEs).³ Here we present two cases of metastatic non-small-cell lung cancer (NSCLC) demonstrating how immunotherapy can be the angel and demon of cancer medicines.

Case 1

A 50-year-old Chinese man, never smoker, presented to the hospital with a 1-month history of cough, haemoptysis and weight loss in July 2017. Chest X-ray (CXR) showed a left upper zone mass. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET-CT scan showed left upper lobe tumour with evidence of right cervical, mediastinal and left hilar lymph node involvement. (Figure 1) MRI brain showed left occipital metastasis. (Figure 2) Bronchoscopic tumour biopsy was obtained. Immunohistochemical staining was positive for TTF1 and napsin, and negative for CK5/6 and p63, favouring the diagnosis of adenocarcinoma. The tumour was negative for EGFR and ALK mutations. PD-L1 staining showed a Tumor Proportion Score (TPS) of 5 percent. Next-generation sequencing showed HER2 kinase mutation, STAT3 E616K mutation, CDK2 A/B mutation, microsatellite stable and intermediate tumour mutation burden.

The patient was treated with carboplatin, pemetrexed and pembrolizumab every 3 weeks for six cycles. The treatment was well tolerated with no chemotherapy-related complications or IRAEs. He also received stereotactic radiosurgery for brain metastasis. Carcinoembryonic antigen (CEA) dropped from a pretreatment level of 123 ng/mL to 1.5 ng/mL. (Figure 3) ¹⁸F-FDG PET-CT showed low activity of the lung lesion and the previously seen lymph nodes, indicating good treatment response. (Figure 4) Reassessment MRI brain showed resolution of the occipital lesion. He was then switched to maintenance therapy with pemetrexed and pembrolizumab every 3 weeks. (Figure 5)

The patient has resumed work and continued to enjoy recreational sports. As of April 2019, he has survived for 21 months since diagnosis with full recovery of function.

Case 2

A 47-year-old Chinese woman, never smoker, presented to the private sector in November 2015 with metastatic NSCLC with involvement of the liver, skeletal system, bilateral adrenals, thyroid and the peritoneum. Excisional biopsy of a left axillary nodule showed metastatic carcinoma. Immunohistochemical staining was positive for TTF1 and napsin, favouring the diagnosis of adenocarcinoma. EGFR mutation was positive with exon 19 deletion. Immunostaining for ALK was negative.

Gefitinib was started in December 2015 and discontinued 1 month later due to clinically progressive disease. PD-L1 of the tumour was found to be high in a private laboratory (exact TPS not available). Nivolumab every 3 weeks was started in February 2016, with disease response seen on ¹⁸F-FDG PET-CT scan 5 months later. Her tumour marker was never markedly raised. Her disease remained under control until 23 months later, with isolated progression found in the primary lung lesion. Radiotherapy to the lesion for abscopal effect was offered but declined by the patient. She opted for a break in nivolumab therapy and received dendritic cell therapy in Germany.

The patient was emergently admitted to Queen Mary Hospital 3 months later in February 2019 with palpitation. Electrocardiography showed supraventricular tachycardia. CXR showed a globular heart shadow. (Figure 6) Urgent CT pulmonary angiography showed pulmonary embolism and 4 cm pericardial effusion, which was noted to have a tamponade effect on echocardiogram. Pericardiocentesis was performed, yielding 650 mL of serosanguinous fluid, which was neutrophil predominant and negative for malignant cells. (Figure 7) There was no growth from the pericardial fluid. Low molecular weight heparin was subsequently given for the pulmonary embolism. She later developed left-sided pleural effusion. (Figure 8) There was no evidence of sepsis. In view of the pericardial fluid findings, IRAE was suspected. Prednisolone 20 mg daily was given, with reduction in pleural effusion 4 days later. Prednisolone was tapered over 8 weeks, with complete resolution of the pleural effusion without need for pleurocentesis. (Figure 9) No recurrence of pericardial effusion was noted either. There was no evidence of other IRAEs.

The patient is continuing with her break from immunotherapy to date. There is no evidence of further disease progression or recurrence of IRAEs.

Discussion

Platinum-based chemotherapy is the first line of treatment for patients with metastatic NSCLC. There have been attempts to improve this treatment approach. The addition of pembrolizumab to chemotherapy was shown to improve overall survival (OS) and progression-free survival (PFS) vs placebo plus chemotherapy.³ In the double-blind, phase III, randomized KEYNOTE-189 trial, the pembrolizumab-chemotherapy regimen demonstrated benefit in patients with untreated, metastatic non-squamous NSCLC without sensitizing EGFR or ALK mutations, in all PD-L1 TPS subgroups. OS rate at 12 months was superior with pembrolizumab-chemotherapy vs placebo-chemotherapy (69.2 percent vs 49.4 percent). Median PFS was 8.8 months in the pembrolizumab-chemotherapy group vs 4.9 months in the placebo-chemotherapy group. There was no increase in incidence of IRAEs in the pembrolizumab-chemotherapy arm compared with previous data on pembrolizumab monotherapy.^4-6

Our first patient presented with metastatic NSCLC with PD-L1 TPS of 5 percent, which indicated a small chance of benefit from single-agent PD-1 and PD-L1 inhibition.⁴ He achieved good disease control from the pembrolizumab-chemotherapy combination. The regimen was well tolerated. No adverse effects from the immunotherapy and chemotherapy were experienced.

IRAEs are defined as adverse incidents potentially mediated by an immunological reaction.⁷ While pneumonitis and colitis are the two most commonly reported IRAEs, almost every organ can be affected. Pleural and pericardial effusion, experienced by our second patient, were described as rare but life-threatening toxicities of immunotherapies. Management of severe IRAEs includes suspension or termination of immunotherapy and use of immunosuppressive therapies (eg, corticosteroid). As dosing and duration of immunotherapy do not correlate strongly with its efficacy, the option of suspension or termination of these agents should be considered in cases of severe IRAEs. If corticosteroid is employed, gradual tapering of dosage is recommended to avoid relapse of the adverse events.

Our second case, unfortunately, suffered from less common IRAEs requiring both interventional (pericardiocentesis) and pharmacological (prednisolone) treatment. The adverse events responded to a gradually tapering steroid regimen. She recovered from the potentially life-threatening events.

These two cases illustrate the angelic and demonic sides of immunotherapy in the treatment of metastatic NSCLC. Effective use of immunotherapy-containing regimens provides desirable oncological outcome, allowing patients to regain full function and quality of life. Yet the potential adverse effects of immunotherapy have to be communicated to the patients, anticipated by the treating oncologists and managed appropriately.