Presentation and investigations
A 71-year-old male former smoker, who quit smoking in 2014, presented with cough in February 2015. CT and PET-CT scans in March 2015 showed T4N0M0 disease (stage IIIA), with an 8 cm hypermetabolic soft tissue mass at the right upper lobe (RUL) of the lung. Mild activity was also noted in the right hilar lymph node region.
Biopsy showed pan–wild-type squamous cell carcinoma. PD-L1 status was unknown as PD-L1 testing was not routinely performed at that time.
Treatment and response
In view of unresectable stage IIIA disease, the patient was commenced on two cycles of carboplatin plus docetaxel (TC) in May 2015, followed by TC-based concurrent chemoradiation therapy (cCRT). PET-CT scan in June 2015 showed partial response. The patient completed cCRT in September 2015.
However, the patient’s carcinoembryonic antigen (CEA) level became elevated 2 months later. PET-CT scan revealed progressive disease (PD) with new lung and pleural lesions.
Gemcitabine and cisplatin (GC) were started for metastatic disease in December 2015, which resulted in stable disease. The patient requested for GC discontinuation in March 2016 (after four cycles) due to intolerable rash and fatigue.
PET-CT scan in July 2016 showed PD with enlarging right middle lobe lesion and presence of lymph node metastases at the right posterior mediastinum. (Figure 1A)
After discussion, the patient agreed to commence nivolumab (200 mg every 2 weeks) monotherapy in August 2016. While he tolerated the first and second cycles very well with only grade 1 skin rash, sudden-onset shortness of breath (SOB) was reported after the third cycle.
As pneumonitis was suspected, the patient was urgently admitted. He was prescribed oral prednisolone and antibiotics upon admission, while urgent CT scan was arranged.
Chest X-ray was clear, and urgent CT scan revealed pulmonary embolism in the upper segmental branch of the right pulmonary artery. As pneumonitis was ruled out, the patient was continued on nivolumab while prednisolone and antibiotics were stopped. Low-molecular-weight heparin was also prescribed for treatment of pulmonary embolism, and was subsequently changed to oral rivaroxaban.
The patient had been on nivolumab for 2 years and completed the last cycle in July 2018. CT scan in December 2018 showed persistent partial response with residual lesions in the RUL. (Figure 1B)
As of the latest follow-up in April 2019, no evidence of PD and symptoms was noted.
Discussion
The present case illustrates durable response (>2.5 years) to nivolumab in a patient with relapsed metastatic squamous cell lung cancer.
The patient presented with stage IIIA disease that was initially managed with standard TC-based cCRT. PD was noted after both cCRT and GC-based chemotherapy. He subsequently received the PD-1 inhibitor nivolumab for disease control in view of failure of two lines of chemotherapy, absence of EGFR or ALK mutations, unknown PD-L1 expression status, and squamous cell histology of the tumour.
The efficacy and safety of nivolumab in the second-line non-small-cell lung cancer (NSCLC) setting was demonstrated in the phase III CheckMate 017 , CheckMate 057 and CheckMate 078 studies, with CheckMate 017 designated for squamous NSCLC.1-3
In the CheckMate 017 study, 272 NSCLC patients who had disease progression during or after first-line chemotherapy were randomized to receive nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. The primary endpoint of overall survival (OS) was significantly longer with nivolumab vs docetaxel (median, 9.2 months vs 6.0 months; hazard ratio [HR], 0.59; 95 percent confidence interval [CI], 0.44 to 0.79; p<0.001). Notably, PD-L1 expression was found to be neither prognostic nor predictive of nivolumab benefit.1
The study design of CheckMate 057 was similar to that of CheckMate 017, except that it recruited patients with nonsquamous NSCLC instead. Median OS was significantly longer with nivolumab vs docetaxel (12.2 months vs 9.4 months; HR, 0.73; 96 percent CI, 0.59 to 0.89; p=0.002). Likewise, OS benefit was observed regardless of PD-L1 expression levels.2
A substantial proportion of NSCLC patients achieved long-term survival with nivolumab, according to a pooled analysis of four nivolumab studies (CheckMate 003, 063, 017 and 057) presented at the American Association for Cancer Research (AACR) Annual Meeting 2019. The pooled analysis of the CheckMate 017 and 057 trials showed that 4-year overall OS rate almost tripled among those treated with nivolumab vs docetaxel (14 percent vs 5 percent). (Figure 2) Plateauing of the OS curve was observed in the nivolumab arms of the above analyses.4 The pooled analysis of CheckMate 017 and CheckMate 057 represents the longest follow-up from phase III randomized trials of previously treated NSCLC patients treated with Immuno-Oncology therapy.
Similar to our patient who had durable response to nivolumab treatment, the pooled analysis showed a higher 4-year OS rate in patients who achieved complete or partial response vs stable disease vs PD with nivolumab (58 percent vs 19 percent vs 4 percent).3 The 4-year OS rate was higher among complete or partial responders to nivolumab vs docetaxel (58 percent vs 12 percent).4
While immunotherapy provides tremendous survival benefits, clinicians should stay vigilant about immune-related adverse events, such as pneumonitis. Although the rate of grade ≥3 pneumonitis was low in studies, it is potentially fatal.1,2 Clinicians should be alert if patients develop pneumonitis-related symptoms including cough and SOB. In such cases, immunotherapy should be terminated if needed. In our patient who experienced SOB after three cycles of nivolumab, urgent admission was arranged for close monitoring and confirmatory tests, and anticoagulant was prescribed once pulmonary embolism was identified as the cause of SOB. As a result, nivolumab was continued in our patient.
