Use of a PD-1 inhibitor plus chemotherapy in a patient with advanced NSCLC and high PD-L1 expression
In February 2017, a 57-year-old male smoker presented with asphyxia and an inability to walk. His oxygen saturation level was 89 percent on room air, necessitating 10 L/min of supplemental oxygen. Initial immunohistochemistry staining showed poorly differentiated lung carcinoma.
A PET scan was not feasible as the patient was unable to lie flat. Hence, a rapid noncontrast CT scan was performed, revealing bilateral pleural metastases, bilateral adrenal metastases, peritoneal metastases and diffuse bone metastases affecting the whole spine and pelvis. There were also multiple bilateral lung metastases and lymphangitic carcinomatosis mainly affecting the right lung. In addition, there were extensive metastases and lymphadenopathy in the entire mediastinum and both hilar regions, along with matted lymph node metastasis in the right supraclavicular fossa.
In view of the extent and severity of his disease, it was thought that his breathing difficulty was caused by obstruction of the superior vena cava and inability to walk was due to metastatic spinal cord compression.
Genetic assays performed on lymph node biopsy were negative for druggable mutations in EGFR, ALK, ROS1, HER2, c-MET, RET or BRAF. Further testing revealed a high level of PD-L1 protein expression.
Results of further immunohistochemical analysis were positive for TTF-1 and negative for napsin A and p63. A diagnosis of nonsquamous non-small-cell lung cancer (NSCLC) was made.
Management and response
Immediate treatment with diuretic and steroid was given to the patient to relieve symptoms of asphyxia.
As per the KEYNOTE-189 study protocol, combination treatment with pembrolizumab plus carboplatin and pemetrexed was initiated while awaiting results of PD-L1 molecular testing. Granulocyte colony-stimulating factor (G-CSF) was given for prophylaxis of leukopenia.
Following the first treatment cycle, the patient reported significant relief of breathlessness, with his oxygen requirement reduced to 3 L/min. Due to amelioration of symptoms and ability to assume a horizontal position, a low-dose CT scan of the thorax was performed, which showed significant shrinkage of the primary tumour and mediastinal lymph nodes.
The patient completed four cycles of combination treatment at 3-week intervals. A PET-CT scan performed in May 2017 showed considerable improvement in all lesions, including absence of metastases in the bone, adrenals and peritoneum, and resolution of pericardial effusion. The primary tumour in the lung had shrunk to 1.6 cm, with further improvements in metastatic lesions within the lung. Significant improvement was also noted in lymphadenopathy in the lateral mediastinal and right supraclavicular regions. The matted mediastinal node remained large with a total diameter >6 cm. (Figure)
In view of the patient's condition, a decision was made to treat residual disease with a discretionary course of radiotherapy along with four cycles of single-agent pembrolizumab maintenance therapy that lasted till July 2017. The patient tolerated the treatment well without fever, skin rash, diarrhoea or any serious adverse effects, such as leukopenia or thrombocytopenia. There was also no evidence of immune-related adverse events, such as pneumonitis.
Pembrolizumab maintenance was continued until August 2019 and was stopped upon completion of 2 years of treatment, The patient’s condition remained well controlled.
Targeted therapies have revolutionized the treatment of advanced NSCLC with druggable mutations (eg, EGFR, ALK, ROS1). However, for patients who lack such genetic alterations, immune checkpoint inhibitors that block PD-1 or PD-L1 have emerged as effective treatment options. The level of PD-L1 expression can be used as a surrogate marker for treatment response to PD-1 inhibitors (eg, pembrolizumab) in these patients.
Pembrolizumab as monotherapy is currently the preferred frontline treatment (over chemotherapy) for patients with advanced nonsquamous NSCLC with PD-L1 expression of ≥50 percent and nodriver mutations.1 This is supported by the KEYNOTE-024 study, which demonstrated improved survival outcomes with pembrolizumab vs platinum-based doublet chemotherapy in high PD-L1–expressing advanced NSCLC without
EGFR or ALK aberrations. The median overall survival (OS) was 30 months with pembrolizumab compared with 14.2 months with chemotherapy (hazard ratio [HR], 0.63; p=0.002), and the 2-year OS rates were 51.5 percent and 34.5 percent, respectively.2,3 For patients who are not high PD-L1 expressors, combinations of immunotherapy agents (anti–PD-L1 plus anti–CTLA-4) or immunotherapy plus standard chemotherapy have been shown to prolong survival. The KEYNOTE-189 study demonstrated improvement in OS across all strata of PD-L1 expression (<1 percent, 1–49 percent and ≥50 percent) with the addition of pembrolizumab to platinum-doublet chemotherapy in patients with metastatic nonsquamous NSCLC.4 According to current National Comprehensive Cancer Network (NCCN) guidelines, pembrolizumab in combination with carboplatin and pemetrexed isalso the preferred regimen for NSCLC patients with tumours without druggable mutations where <50 percent of cells express PD-L1.
In the IMpower150 study, combining immunotherapy with bevacizumab plus chemotherapy conferred superior survival benefits regardless of PD-L1 expression.5 Similarly, in another phase III trial, the combination of two immune checkpoint inhibitors demonstrated superior survival compared with chemotherapy alone, even in a subset of NSCLC patients with PD-L1 expression <1 percent.6
In addition to the presence or absence of driver mutations and the level of PD-L1 expression, the patient’s overall clinical picture should also be taken into consideration when deciding on the optimal treatment strategy. Rapidly progressing or very extensive disease with impending organ failure may warrant the addition of chemotherapy to pembrolizumab in the first-line setting. Unlike chemotherapy, which has a direct tumouricidal effect, immunotherapy is commonly associated with a delayed treatment benefit, possibly because it takes time to mount an effective antitumour immune response. This is reflected in the OS curves in KEYNOTE-024, where a proportion of patients did better with chemotherapy than with immunotherapy alone in the first month of the trial.2,4-6
In addition to enabling a rapid antitumour response, chemotherapy may also improve the depth of response to immunotherapy by facilitating the release of neoantigens through tumour cell death.
Treatment of advanced NSCLC should be tailored to the needs of individual patients. Being a strong PD-L1 expressor, our patient would be suitable for pembrolizumab monotherapy. However, the immediate prognosis with monotherapy would be very poor due to the presence of life-endagering asphyxia and rapidly progressive spinal cord compression, both of which called for a quick response. Hence, chemotherapy was co-administered with pembrolizumab.