Biomarker testing and management of immune-related adverse events are key roles for pharmacists.
As checkpoint inhibitors become the new standard of care for patients with non–small cell lung cancer (NSCLC), pharmacists can play a vital role in selection and management, according to panelists in a Pharmacy Times Continuing Education session at the American Society of Health-System Pharmacists (ASHP) 2022 Midyear Clinical Meeting.
More than 222,000 individuals will have received a diagnosis of lung cancer in 2021, the vast majority of which are NSCLC. Most NSCLC cases are unresectable or metastatic at diagnosis, illustrating the need for strong therapeutic options, according to the panel. Targeted therapies and immune checkpoint inhibitors (ICIs) have improved survival rates in NSCLC, despite its position as the leading cause of cancer deaths in the United States.
“We’ve seen many developments over the past 10 years or so, with the advent of targeted therapies and the checkpoint inhibitors, which have drastically improved survival outcomes for patients with metastatic non–small cell lung cancer,” said presenter Allison Schepers, PharmD, BCOP. “However, we’ve made a lot of progress but we still have some long ways to go, as lung cancer remains the leading cause of cancer death in this country.”
The treatment paradigm for metastatic NSCLC includes chemotherapy, immunotherapy, chemoimmunotherapy, and targeted therapies. In particular, ICIs are commonly used for metastatic NSCLC, including in the front-line setting. For optimal usage, however, molecular testing and programmed death-ligand 1 (PD-L1) testing are recommended for all patients with metastatic NSCLC.
Cancer cells and tumor-infiltrating immune cells express the programmed cell death-1 (PD-1) ligand, and correlation between PD-L1 expression and the efficacy of ICIs varies widely among solid tumor malignancies. Therefore, PD-L1 testing has become an essential part of first-line treatment selection for metastatic NSCLC.
“Therapy selection for non–small cell lung cancer is not a 1-size-fits-all approach,” Schepers said. “The days of giving platinum chemotherapy to everyone are done.”
The results of PD-L1 testing significantly influences therapy selection. According to National Cancer Care Network (NCCN) guidelines for first-line therapy in metastatic NSCLC, a PD-L1 of 50% or greater lends itself toward therapy with pembrolizumab, atezolizumab, and cemiplimab. Additionally, in nonsquamous NSCLC cases, NCCN guidelines suggest platinum chemotherapy plus pemetrexed and pembrolizumab. In squamous cases, guidelines recommend carboplatin plus paclitaxel or nabpaclitaxel, as well as pembrolizumab.
For PD-L1 tests between 1% and 49% as well as <1%, guidelines suggest platinum chemotherapy plus pemetrexed and pembrolizumab in nonsquamous NSCLC, and carboplatin plus paclitaxel or nab-paclitaxel and pembrolizumab in squamous NSCLC.
Despite its widespread use, there are challenges to the use of PD-L1 as a biomarker. In particular, variability in PD-L1 depending on sample site and timing, discordance among the available tests, a lack of standard definition for PD-L1 positivity among disease states or ICIs, and a lack of optimal treatments for PD-L1 between 1% and 49% all pose challenges.
When selecting first-line treatment for NSCLC, key considerations include histology, targetable biomarker, PD-L1 expression, performance status, metastatic sites, and other patient factors. Various clinical trials and treatments have shown promise for different patient populations, according to the panel.
For example, results of the KEYNOTE-024 trial of pembrolizumab found that monotherapy improved overall survival (OS) compared to chemotherapy in metastatic NSCLC with a PD-L1 of more than 50%. Similarly, results of the EMPOWER-Lung 1 trial of cemiplimab-rwlc found that monotherapy improved OS compared to chemotherapy in the same patient population.
In patients with metastatic NSCLC with tumor cells >50% or IC >10%, the IMPOWER-110 trial of atezolizumab found that monotherapy improved OS compared to chemotherapy; however, OS did not differ in other PD-L1 groups.
Immunotherapy monotherapy has been examined extensively in NSCLC with PD-L1 <50%. The IMPOWER-110 trial examined any PD-L1 subgroup but a formal OS comparison was not performed. The CHECKMATE-026 trial of nivolumab found a median OS of 14.4 months in the treatment arm versus 13.2 months in the control arm. Additionally, the KEYNOTE-042 trial with pembrolizumab found a median OS of 13.4 months vs 12.1 months in the treatment arm and control arm, respectively.
Still other trials have found promise with combination regimens of chemoimmunotherapy. For example, the KEYNOTE-189 trial investigated chemotherapy with or without pembrolizumab in stage 4 NSCLC patients with any PD-L1 expression and nonsquamous histology. The results found that the combination improved OS compared with chemotherapy alone and OS was significantly longer in PD-L1 >50%, between 1% and 49%, and <1%.
“We have several regimens to discuss, and I think these regimens are very interesting and exciting,” Schepers said.
Similarly, the KEYNOTE-407 trial investigated chemotherapy with or without pembrolizumab in stage 4 NSCLC with any PD-L1 expression and squamous histology. This trial found that the combination improved OS compared to chemotherapy alone, with an OS of 17.1 months in the combination arm vs 11.6 months in the chemotherapy alone arm.
The EMPOWER-Lung 3 trial examined chemotherapy with or without cemiplimab in patients with advanced or stage 4 NSCLC, any PD-L1 expression, and squamous as well as nonsquamous histology. The trial found that the combination improved OS compared to chemotherapy alone, with an OS of 21.9 months in the treatment arm vs 13 months in the control arm. Additionally, the ORR was 44.3% in the treatment arm versus 22.7% in the control arm.
Other recommended chemotherapy and ICI regimens can include atezolizumab, bevacizumab, carboplatin, and paclitaxel (as seen in the IMPOWER 150 trial) or nivolumab, ipilimumab, and platinum doublet chemotherapy (as seen in the CHECKMATE 9-LA trial).
ICI can also play a role in maintenance therapy for NSCLC, which is administered after 4 to 6 cycles of first-line therapy for those whose tumors have not progressed. Continuation maintenance immunotherapy is recommended for 2 years, if tolerated, for all first-line immunotherapy regimens with or without chemotherapy.
ICI monotherapy may also be used in the second-line setting. Pembrolizumab has been approved in this setting for PD-L1 of 1% or greater, and nivolumab and atezolizumab are both approved regardless of PD-L1 status. However, if an ICI was administered as first-line therapy, it is not indicated in the second-line setting.
With all of these various trial results and guidelines, the panelists emphasized that treatment decisions must be individualized and can vary based on many factors. These factors can include severity and control of autoimmune disease, risk of disease flare or graft rejection, and availability of treatments.
Schepers concluded that future research directions for ICIs include novel mechanisms, combinations with targeted therapy and ICI, improved therapy selection with novel biomarkers, optimal sequencing, and research into the use of ICIs in special patient populations.
A key area in which pharmacists should be involved is in the management of checkpoint inhibitor pneumonitis (CIP), according to presenter Jordan McPherson, PharmD, MS, BCOP. As with all immune-related adverse events (AEs), constant monitoring and awareness is essential.
“There is a need for constant awareness of the patient, and clinicians have [to be aware of] the possibility of immune toxicity occurrence after ICI,” McPherson said.
The incidence of CIP is between 3% and 5%, making it one of the most common immune-related AEs. Patients with PD-1 and PD-1 plus CTLA-4 ICI are at an increased risk, and CIP has a mortality risk between 10% and 17%. Additionally, identifying CIP can be challenging because it has no specific symptoms, radiologic findings, or serological markers.
“We don’t know exactly why it occurs [and] there are many different proposed mechanisms,” McPherson said. “Risk factors are kind of interesting as well because there are many different things that could be going on.”
Some symptoms can include a dry cough, shortness of breath, fatigue, reduced activity tolerance, increased oxygen need, fever, and chest pain. Laboratory markers can include elevated C-reactive protein and erythrocyte sedimentation rate.
CIP is graded based on symptoms. Grade 1 CIP is asymptomatic and confined to 1 lobe of the lung of <25% lung parenchyma. Grade 2 has new or worsening symptoms; grade 3 has severe symptoms involving all lung lobes or >50% of lung parenchyma; and grade 4 is characterized by life-threatening respiratory compromise.
“Oxygen indication implies a grade 3 pneumonitis—I think that’s an important thing to note,” McPherson said.
Initial management of CIP includes holding or managing ICI treatment, starting high-dose corticosteroids (prednisone for grade 2 or methylprednisolone for grade 3-4), and potentially empiric broad-spectrum antibiotics if infection has not been fully excluded. For steroid-refractory CIP, clinicians can add a secondary immunosuppressant if there is no improvement after 48 hours.
“This is where I see a lot of people drag their feet—we want to give them more time to respond, want to do more testing and work it out,” McPherson said. “We’re not getting on top of patients fast enough. We’re not getting a secondary aid on board.”
Approximately 2% of CIP cases may involve chronic CIP, defined by 12 or more weeks of immunosuppression. Risk factors for this include lymphocytosis on cell differential of the bronchoscopy and bronchoalveolar lavage fluid sample, as well as organizing pneumonia at the initial CIP diagnosis. Half of chronic CIP cases require long-term steroid use and there is evidence of persistent imaging abnormalities and scarring even in patients whose symptoms resolve.
Taken together, all of the data for ICI suggest that pharmacists have a key role to play in the multidisciplinary team. PD-L1 testing is recommended for all patients with metastatic NSCLC and immunotherapy is part of the first-line therapy for NSCLC in patients without driver mutations or contraindications.
For patients with a PD-L1 of 50% or greater, immunotherapy monotherapy may be used, whereas combination chemotherapy and immunotherapy regimens are preferred for most patients with a PD-L1 of less than 50%. Choosing a specific treatment regimen is based on many factors. Finally, pharmacists should continuously monitor for CIP to rapidly identify and treat it appropriately.
Schepers A, McPherson J, Mohs J. Exploring the New Standard of Care for the Frontline Treatment of Non–Small Cell Lung Cancer. Presented at American Society of Health-System Pharmacists 2022 Midyear Clinical Meeting. December 6, 2022.