Mohamed K. Mohamed, MD
Pembrolizumab (Keytruda) has emerged as a reliable frontline treatment option for patients with metastatic non–small cell lung cancer (NSCLC), but thoracic oncologists need to be aware of potentially severe immune-related adverse events (irAEs), said Mohamed K. Mohamed, MD.
A trio of positive phase III studies—KEYNOTE-024, KEYNOTE-189, and KEYNOTE-407—has led to recent FDA approvals for pembrolizumab in multiple frontline indications. Despite the encouraging survival data and response rates observed in these studies, these irAEs associated with the PD-1 inhibitor need to be considered, said Mohamed, a hematologist/oncologist at Cone Health Medical Group.
“In these trials, the AEs with pembrolizumab were comparable with what was seen in the control arms, but the handling of these toxicities is what makes them unique and challenging,” Mohamed said during a presentation at the 2018 New York Lung Cancers Symposium.
Common AEs observed with the agent are pneumonitis, colitis, hepatitis, nephritis, and severe skin reaction; however, their incidences varied across the 3 pivotal studies. Based on the severity of the AEs, Mohamed noted, pembrolizumab should be withheld or discontinued with the administration of corticosteroids if appropriate.
“Pembrolizumab can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis,” said Mohamed. “Monitor patients for signs and symptoms of infusion-related reactions and for grade 3 or 4 reactions, stop infusion, and permanently discontinue pembrolizumab.”
Severe diarrhea is another AE commonly seen in patients who are treated with other checkpoint inhibitors, Mohamed added, a result of stimulated T cells attacking the colon.
In addition, he said, based on the drug’s mechanism of action, it can also cause fetal harm when administered to pregnant women. Therefore, female patients of reproductive potential should be aware of the potential danger to the fetus.
In the KEYNOTE-189 study, which led to the full August 2018 FDA approval of pembrolizumab in combination with carboplatin/pemetrexed for patients with nonsquamous metastatic NSCLC, a number of irAEs were reported.
In the multicenter, double-blind, phase III trial, more than half of the patients who were treated with pembrolizumab had an interrupted dosing schedule due to AEs and 20% had to discontinue treatment.1
Discontinuation of all drugs because of AEs occurred in 13.8% of patients on the pembrolizumab arm and in 7.9% of those on the placebo arm. The discontinuation rates of pembrolizumab and placebo were 20.2% and 10.4%, respectively. Moreover, there were 6.7% and 5.9% AE-related deaths in the pembrolizumab and control arms, respectively.
The most common AEs that led to permanent discontinuation with the checkpoint inhibitor were pneumonitis (3%) and acute kidney injury (2%), said Mohamed.
Thirteen percent of the patients had neutropenia and 7% had treatment-interrupting fatigue. Other commonly observed AEs were anemia (7%), thrombocytopenia (5%), thrombocytopenia (5%), diarrhea (4%), and dyspnea (2%). Notably, a higher incidence of fatigue was noted in the patients in the control arm who were treated with chemotherapy alone.
In KEYNOTE-189, the addition of pembrolizumab to chemotherapy demonstrated a 51% reduction in the risk of death versus chemotherapy alone. One-year overall survival (OS) rates with the combination were 69.2% compared with 49.4% in the control arm. Median OS was not reached in the pembrolizumab arm and was 11.3 months in those who received chemotherapy alone.
For patients who progress on pembrolizumab and chemotherapy as a first-line treatment, the National Comprehensive Cancer Network guidelines recommend second-line therapy with docetaxel with or without ramucirumab (Cyramza), or gemcitabine monotherapy.
Data of the phase III KEYNOTE-407 trial furthered researchers’ knowledge of the potency and tolerability of pembrolizumab. The phase III trial resulted in the October 2018 FDA approval of the monoclonal antibody to be used in combination with carboplatin and paclitaxel/nab-paclitaxel (Abraxane) for the treatment of patients with squamous metastatic NSCLC, based on a 36% reduction in the risk of death with the addition of pembrolizumab.2
In 101 patients treated with pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, 15% had to permanently discontinue treatment and 43% had their treatment interrupted due to AEs. The most common AEs that led to discontinuation of treatment were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%).
“The adverse reactions observed in KEYNOTE-407 were similar to KEYNOTE-189 with the exception that increased incidences of alopecia and peripheral neuropathy were observed in the experimental arm of KEYNOTE-407,” explained Mohamed.
Alopecia and peripheral neuropathy were reported in 47% and 31% of patients who were treated in the pembrolizumab arm, respectively. Other common serious AEs observed in this study were pneumonia (6%), febrile neutropenia (6%), and urinary tract infection (3%).
In a pooled data analysis of 2799 patients enrolled in the 3 KEYNOTE trials, pneumonitis was determined to occur more frequently in patients with a history of prior thoracic radiation (6.9%) compared with those without (2.9%). For patients with pneumonitis, Mohamed stressed that physicians should administer corticosteroids for AEs that are grade 2 or higher incidences. Pembrolizumab should be withheld temporarily with grade 2 AEs and permanently discontinued for recurrent AEs that are grade 2 or higher.
Moreover, patients should also be continuously monitored for severe skin reactions, particularly Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be fatal in some cases.
For other clinically important immune-mediated AEs, corticosteroids should be administered as standard management. In the small percentage of patients who do not respond to this treatment, other systemic immunosuppressants can be considered, he concluded.
- Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Eng J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
- Paz-Ares LG, Luft A, Tafreshi A, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Eng J Med. 2018;379:2040-2051. doi: 10.1056/NEJMoa1810865.