Combination of anti–PD-1 immunotherapy and chemotherapy in a patient with metastatic NSCLC with no targetable mutations and minimal PD-L1 expression
History and presentation
A 63-year-old male ex-smoker presented with back pain to an orthopaedic clinic in December 2019. MRI revealed bone metastasis at the T12 thoracic spinal segment, with left paraspinal tumour compression on the nerve roots within the neural foramina, causing neuropathic and back pain. Lumbar decompression surgery with spinal stabilization was performed by an orthopaedic surgeon in February 2020. Histology test indicated metastatic adenocarcinoma of lung origin, and subsequent PET-CT scan showed an 8 cm lung tumour in the left upper lobe. The patient was diagnosed with nonsquamous non-small-cell lung cancer (NSCLC) with solitary bone metastasis at the T12 thoracic vertebra. No additional distant metastasis or mediastinal lymph node involvement was detected.
Treatment and response
The patient was referred to our clinic for cancer treatment. Stereotactic body radiotherapy (SBRT; with 3 fractions of high-dose radiation) targeting the bone metastasis was performed in February 2020. He recovered well from the procedure, which helped relieve back pain and enabled him to walk unaided. Lobectomy was carried out by a cardiothoracic surgeon in March 2020 to remove the 8 cm primary NSCLC in the left upper lobe. Histology tests on tumour biopsy reviewed absence of EGFR, ALK or ROS1 mutations, and a tumour proportion score (TPS) of <1 percent for programmed death-ligand 1 (PD-L1) expression. The patient remained well after lobectomy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and a carcinoembryonic antigen (CEA) level of about 360 ng/mL (reduced from a level of >10,000 ng/mL prior to SBRT and lobectomy). Follow-up PET-CT scan detected residual tumour at the T12 thoracic vertebra.
The patient started systemic combination therapy with pemetrexed (500 mg/m2, Q3W), carboplatin (target AUC=5 mg/min/mL, Q3W) plus the PD-1 inhibitor pembrolizumab (200 mg fixed dose, Q3W) in March 2020. His CEA level further decreased to 2 ng/mL and PET-CT scan showed complete remission with no residual tumour after four cycles of the combination therapy with pembrolizumab and chemotherapy. (Figure) The combination treatment was well tolerated, without any significant adverse events (AEs).
The patient is currently receiving maintenance therapy with pembrolizumab plus pemetrexed (Q3W) and has completed four cycles of maintenance treatment to date. His disease remains stable (CEA level remains at about 2 ng/mL), he is able to walk unaided and has resumed normal daily activities, including returning to work. Potential AEs such as pneumonitis will continue to be monitored with chest X-ray at each treatment visit, and the required duration of therapy will be evaluated at 1 year since commencing maintenance treatment.
While PD-L1 tumour expression level has some correlation with the level of response to PD-1/PD-L1 checkpoint inhibitors, patients with negligible PD-L1 expression (ie, <1 percent) also derive benefits from anti–PD-1/PD-L1 immunotherapy, particularly in combination with chemotherapy. Chemotherapeutic agents enhance the release of tumour antigens through inducing cell death, thereby improving tumour immunogenicity and synergistically enhancing the efficacy of immune checkpoint inhibitors, such as pembrolizumab.1
Immunochemotherapy with pembrolizumab is the standard first-line treatment conferring durable survival benefits to patients with metastatic squamous and nonsquamous NSCLC lacking targetable (EGFR or ALK) mutations, regardless of PD-L1 expression.2,3
Approximately one-third of patients with metastatic nonsquamous NSCLC in the randomized, double-blind, phase III KEYNOTE-189 trial had a TPS <1 percent. Protocol-specified final analysis, after a median follow-up of 31.0 months, showed that chemotherapy (pemetrexed and a platinum agent) plus pembrolizumab substantially improved median overall survival (OS) vs chemotherapy plus placebo (22.0 months vs 10.6 months; hazard ratio [HR], 0.56; 95 percent confidence interval [CI], 0.46 to 0.69) in patients with previously untreated metastatic nonsquamous NSCLC, irrespective of PD-L1 expression. The 24-month OS rates were 45.7 percent vs 27.3 percent, respectively. In the subset of patients with TPS <1 percent, such as our patient, the median OS was 17.2 months vs 10.2 months in the chemotherapy plus pembrolizumab vs chemotherapy plus placebo group.2
Furthermore, the addition of pembrolizumab to chemotherapy also improved first and second median progression-free survival (PFS) (defined as time from randomization to objective tumour progression on next-line treatment or death from any cause, whichever occurred first) vs chemotherapy alone, irrespective of PD-L1 expression (intention-to-treat population: PFS1, 9.0 months vs 4.9 months; HR, 0.49; 95 percent CI, 0.41 to 0.59; PFS2, 17.0 months vs 9.0 months; HR, 0.50; 95 percent CI, 0.41 to 0.61). In the TPS <1 percent subset, PFS1 was 6.2 months and PFS2 was 12.6 months in patients treated with chemotherapy plus pembrolizumab, vs 5.1 months and 8.1 months, respectively, in patients receiving chemotherapy plus placebo.2
Safety profile was comparable between the chemotherapy plus pembrolizumab group and the chemotherapy plus placebo group (grade 3–5 AE rate, 72.1 percent vs 66.8 percent), indicating that the majority of AEs were due to the backbone chemotherapy regimen. Immune-mediated AEs and infusion-related reactions of any grade occurred in 27.2 percent and 12.9 percent of patients in the pembrolizumab and placebo groups, respectively.2
As well as the KEYNOTE-189 study, pembrolizumab plus chemotherapy was also evaluated in patients with metastatic squamous NSCLC in the multicentre, randomized, double-blind, placebo-controlled, phase III KEYNOTE-407 trial.3 The KEYNOTE-407 China Extension Study evaluated outcomes in 125 patients, 48 of whom (38 percent) had PD-L1 TPS <1 percent, enrolled from mainland China and, after a median follow-up of 10.4 months, demonstrated efficacy and safety that were comparable between mainland Chinese patients and the global population, with no new safety signals identified in the Chinese population, lending further support to the use of pembrolizumab plus chemotherapy as a first-line treatment in local patients with metastatic NSCLC, regardless of PD-L1 expression.3,4
While our patient did not experience any immune-related AEs, patients receiving immunotherapy should be closely monitored for signs and symptoms of pneumonitis. Immunochemotherapy and chemotherapy should be considered with caution in patients with active immune disease or patients deemed unfit for chemotherapy. Although guidelines (such as those from the National Comprehensive Cancer Network and European Society for Medical Oncology) can help guide treatment decisions in the management of NSCLC, optimal therapeutic strategy should be individualized according to the patient’s overall health, drug tolerability and disease characteristics (such as tumour staging and histology features), and the latest clinical evidence.
This case illustrated the efficacy and safety of combination pembrolizumab plus chemotherapy as a first-line treatment in a patient with metastatic nonsquamous NSCLC without actionable mutations and PD-L1 expression. The patient achieved complete remission and tolerated the combination treatment well without experiencing any significant AEs.