Second-line use of a PD-L1 inhibitor plus a VEGF inhibitor and chemotherapy in an elderly patient with metastatic NSCLC
Presentation and history
A 75-year-old gentleman presented to our clinic in February 2019, following a routine check-up showing an elevation of carcinoembryonic antigen (CEA) to 2,900 ng/mL (normal range, ≤3 ng/mL). The patient was an ex-smoker who quit approximately 10 years ago, having smoked 10–20 cigarettes a day for 40 years prior to quitting. He had diabetes mellitus (DM) and hypertension and was receiving appropriate medication for both.
One week after presenting to our clinic, the patient’s CEA level rose to 5,600 ng/mL. Subsequent PET-CT scan revealed a very large (diameter, 5.7 cm), hypermetabolic (SUVmax, 18) tumour in the left upper lobe of the lung. No other nodules were observed in the rest of the lungs. However, pleural effusion was noted in the left pleural cavity, along with a few mediastinal lymph nodes in the aorto-pulmonary region and multiple liver metastases, abdominal lymph node involvement, and rib metastases.
Bronchoscopy biopsy confirmed pulmonary adenocarcinoma with an EGFR exon 21 L858R point mutation. The patient’s PD-L1 expression level was 20 percent; no other genetic abnormalities were recorded. He was diagnosed with stage IV non-small-cell lung cancer (NSCLC).
Chemoradiation and subsequent immunotherapy
Treatment with the first-generation EGFR tyrosine kinase inhibitor (TKI) gefitinib was commenced in March 2019.
After 5 months of treatment, repeat PET-CT scan demonstrated significant shrinkage of the primary tumour, from 5.7 cm to 3.5 cm in diameter. The CEA level dropped from 5,600 ng/mL to 72 ng/mL. His left pleural effusion subsided. The mediastinal lymph nodes showed very good response in terms of size and metabolic activity reduction as well. Distant metastases in the liver and abdominal lymph nodes also showed a very good response, and the rib metastases demonstrated a drop in metabolic activity. Overall, the patient achieved at least a partial response to gefitinib.
In October 2019, 7 months after initiating gefitinib, the patient’s CEA rebounded to 300. Subsequent PET-CT scan revealed progressive disease, with an increase of the primary tumour’s diameter to 6.6 cm and an increase in its metabolic activity to SUVmax of 20. Furthermore, new lesions were identified in the brain and left adrenal gland.
The patient refused a rebiopsy to identify a new EGFRT790M targetable mutation, and this mutation was not identified in a liquid blood biopsy.1
In November 2019, treatment was switched to immunotherapy with a PD-L1 inhibitor, atezolizumab, in combination with an anti-angiogenic agent, the VEGF inhibitor, bevacizumab, and carboplatin-based chemotherapy.
After four treatment cycles, the diameter of the primary lung tumour reduced to 3.3 cm, with a SUVmax of 3.4. The brain metastases demonstrated complete response and were no longer identifiable on MRI. The liver and bone metastases as well as the peripheral lymph nodes produced a very good response. No new lesions were identified. (Figure) The CEA level dropped from 72 ng/mL to ≤20 ng/mL.
Taking the patient’s advanced age into consideration, after four cycles of treatment with atezolizumab, bevacizumab and carboplatin-based chemotherapy, the patient was switched to maintenance with atezolizumab, bevacizumab and pemetrexed.
As of July 2020, the patient has received 10 cycles of treatment, including six maintenance cycles. The patient tolerated treatment very well, without any dose reductions or interruptions. He did not experience any immune-related toxicity and had no thromboembolic events. He patient continues to receive maintenance treatment.
Our patient was initially prescribed first-line treatment with gefitinib based on the presence of EGFR exon 21 L858R point mutation, which is prevalent among Asian patients. When treatment with gefitinib was no longer effective and given his refusal of rebiopsy to identify another targetable mutation (ie, EGFRT790M), the patient was considered for immunotherapy with atezolizumab in combination with bevacizumab and carboplatin-based chemotherapy, on the basis of the phase III IMpower150 trial.
The IMpower150 trial enrolled patients with EGFR mutations and stratified patients by presence of baseline liver metastases. In patients with sensitizing EGFR mutations, including the EGFRL858R mutation discovered in our patient, and patients with baseline liver metastases, which our patient also had, the atezolizumab/ bevacizumab/ carboplatin/ paclitaxel (ABCP) regimen provided overall survival (OS) and progression-free survival (PFS) benefits vs the standard-of-care bevacizumab/ carboplatin/ paclitaxel (BCP) regimen.2
At a median follow-up of 19.6 months, the key subgroup analysis of IMpower150 showed that median OS was not estimable (NE) in patients with sensitizing EGFR mutations receiving ABCP vs 17.5 months in those receiving BCP (hazard ratio [HR], 0.31; 95 percent confidence interval [CI], 0.11 to 0.83).2 These findings compared favourably with the intention-to-treat (ITT) population, with a median OS of 19.8 months vs 14.9 months for ABCP vs BCP (HR, 0.76; 95 percent CI, 0.63 to 0.93).3
In addition, improved median OS with ABCP (13.3 months) vs BCP (9.4 months) was seen in patients with baseline liver metastases (HR, 0.52; 95 percent CI, 0.33 to 0.82). By contrast, the atezolizumab/ carboplatin/ paclitaxel (ACP) regimen did not show improved efficacy or survival vs BCP in these subgroups with sensitizing EGFR mutations.2
In patients with sensitizing EGFR mutations who, like our patient, previously received EGFR TKI therapy, the HR for OS was 0.39 (95 percent CI, 0.14 to 1.07) for ABCP vs BCP. Furthermore, patients who received prior TKI therapy and were treated with ABCP achieved longer PFS vs those on BCP (median, 9.7 months vs 6.1 months; HR, 0.42; 95 percent CI, 0.22 to 0.80).2
In the same subgroup analysis, the objective response rate (ORR) in patients with EGFR mutations was 70.6 percent vs 35.6 percent vs 41.9 percent for ABCP vs ACP vs BCP, with a median duration of response (DoR) of 11.1 months vs 5.6 months vs 4.7 months. Among patients with liver metastases at baseline, the ORR was 60.8 percent vs 26.9 percent vs 41.1 percent, with a median DoR of 10.7 months vs 5.6 months vs 4.6 months.
In the EGFR-positive safety-evaluable population, grade 3/4 adverse events (AEs) were observed in 64 percent of patients in the ABCP group, 68 percent in the ACP group and 64 percent in the BCP group. No EGFR-positive patients in the ABCP group had a grade 5 AE. AEs of special interest, which included immune-related AEs, were observed in 55 percent of patients treated with ABCP, 52 percent of patients on ACP, and 23 percent of patients on BCP.
Given the increased risk of bleeding associated with bevacizumab use, recent (≤3 months) stroke, myocardial infarction, and bleeding or thrombotic tendencies were ruled out prior to commencing treatment in our patient. While his tumour was very large, it was not close to the great vessels, therefore the risk of a bleeding event was not deemed high. His main comorbidities of hypertension and DM were under relatively good control, with home fasting blood glucose level of around 6.0 mmol/l and blood pressure of 125/85 mm Hg.
Bevacizumab has been used for approximately 15 years for treatment of NSCLC in Hong Kong, and has established itself as an efficacious and relatively well-tolerated agent in Asian patients, provided that its use is withheld in patients with underlying risk factors and that existing comorbidities are well controlled.4
Overall, our case demonstrates the very good tolerability and good partial response achieved by the four-agent regimen consisting of atezolizumab, bevacizumab and carboplatin-based doublet chemotherapy in an elderly NSCLC patient with liver metastases with well-controlled underlying comorbidities, after prior treatment with an EGFR TKI.