To assist clinicians in the day-to-day management of their patients, the Society for Immunotherapy of Cancer has developed its first guidelines to help direct immune checkpoint inhibitor treatment of NSCLC.
Roy S. Herbst, MD, PhD
Immunotherapy began replacing cytotoxic chemotherapy as the standard of care in specific non small lung cancer (NSCLC) settings almost as soon as nivolumab (Opdivo) gained initial FDA approval for treatment of the disease in March 2015. Since then, a number of checkpoint inhibitors have also gained approval for treatment of patients with NSCLC. This rapid introduction of immunotherapy into the clinic, however, makes staying abreast of the latest developments difficult for practicing clinicians, creating a need in the field for evidence-based recommendations to help guide treatment decisions.
To assist clinicians in the day-to-day management of their patients, the Society for Immunotherapy of Cancer has developed its first guidelines to help direct immune checkpoint inhibitor (ICI) treatment of NSCLC. Roy S. Herbst, MD, PhD, chief of Medical Oncology at Yale Cancer Center in New Haven, Connecticut, and chair of the Cancer Immunotherapy GuidelinesNSCLC Subcommittee, said the pace of change in the field made it difficult to release the document, which had to be revised constantly to keep up with new developments.
“Look at the progress that’s been made in immunotherapy for lung cancer in just the past few yearsthe field is completely different,” Herbst said. “The guideline is incredibly important. You’re in the clinic; you need to understand how to use immune therapies. Now you have squamous, nonsquamous, first-line, second-line, and so forth. The guideline is an essential part of the whole process.”
Treatment for patients with advanced NSCLC starts with a complete clinical, radiological, and pathological work-up, including determination of tumor histological subtype and molecular analyses to identify targetable driver mutations.
Subcommittee members agreed that all patients with newly diagnosed, advanced NSCLC should undergo routine immunohistochemistry-based testing to determine PD-L1 expression levels.
First-line recommendations include immune checkpoint blockade with pembrolizumab (Keytruda) as a single agent or combined with chemotherapy. Recently, the FDA approved atezolizumab (Tecentriq) in the first-line setting for use in combination with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) in patients with metastatic NSCLC.
Nivolumab and pembrolizumab (single-agent or combination) were recommended for second-line use. The subcommittee also recommended durvalumab (Imfinzi) in the maintenance/adjuvant setting for patients with locally advanced, stage III disease following chemoradiation.1“Clearly, immunotherapy plus chemotherapy is a standard of care in the frontline setting across all PD-L1 subtypes,” Herbst said. “Almost all patients should be getting immunotherapy now in the earliest possible stages.”
Treatment with nivolumab was shown to improve median overall survival (OS) in previously treated patients with advanced squamous or nonsquamous cell NSCLC compared with docetaxel, according to results from several CheckMate trials (TABLE).
The median OS was 9.2 months with nivolumab compared with 6.0 months for docetaxel (HR, 0.59; 95% CI, 0.44-0.79;P<.001) in CheckMate 017, which involved patients with squamous cell lung cancer.
Nivolumab also demonstrated superior median OS compared with docetaxel in CheckMate 057 (12.2 vs 9.4 months; HR, 0.73; 95% CI, 0.60-0.89;P= .002) for patients with NSCLC. The rate of grade ≥3 treatment-related adverse events reported in the 2 trials also favored the nivolumab arms (<10% vs ≈55%).
The subcommittee noted that results from the ongoing phase III CheckMate 227 trial showed that the combination of nivolumab and low-dose ipilimumab (Yervoy) improved median progression-free survival (PFS) compared with chemotherapy in patients with high tumor mutational burden and regardless of tumor PD-L1 expression (HR, 0.58; 97.5% CI, 0.41-0.81;P<.001). Recent results from that trial showed that nivolumab plus chemotherapy improved median PFS compared with chemotherapy alone in patients with low PD-L1 expression (5.6 vs 4.7 months; HR, 0.74; 95% CI, 0.58-0.94).
In the phase Ib KEYNOTE-001 trial (N = 495), pembrolizumab had an overall response rate of 19.4% (95% CI, 16.0-23.2) for patients with advanced NSCLC. Outcomes were superior for patients with high PD-L1 ≥50%, while the other 2 groups, 1% to 49%, and <1%, were similar. In October 2015, the FDA approved pembrolizumab for patients with PD-L1positive, metastatic NSCLC who progressed after receiving platinum-based chemotherapy or targeted agents for ALK- or EGFR-mutation based on results from KEYNOTE-010.
Two years later, the agency expanded that approval to include first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression with no EGFR or ALK mutations based on results from the phase III KEYNOTE-024 trial. Compared with investigators’ choice of platinum-doublet chemotherapy, pembrolizumab demonstrated significantly longer median PFS (10.3 vs 6.0 months; HR, 0.5; 95% CI, 0.37-0.68;P<.001) and a superior 6-month OS (80.2% vs 72.4%; HR, 0.6; 95% CI, 0.41-0.89;P= .005).
The double-blind phase III KEYNOTE-189 study2accrued 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. The patients had no actionable mutations and had not received prior systemic therapy. In the experimental arm, patients received pembrolizumab plus pemetrexed and either cisplatin or carboplatin.
The regimen administered to the control group was identical, except that pembrolizumab was replaced with placebo. Pembrolizumab OS benefit was observed across PD-L1 subgroups, including the <1% expression group (OS, 61.7% vs 52.2%; HR, 0.59; 95% CI, 0.38-0.92), the 1% to 49% cohort (OS, 71.5% vs 50.9%; HR, 0.55; 95% CI, 0.34-0.90), and those with a score of 50% or greater (OS, 73.0% vs 48.1%; HR, 0.42; 95% CI, 0.26-0.68). These findings led to the frontline approval of pembrolizumab for use in combination with standard chemotherapy for patients with metastatic, nonsquamous NSCLC.
In addition, results from the phase III KEYNOTE-407 trial3suggest that adding pembrolizumab to frontline chemotherapy can also provide benefit to patients with advanced, squamous NSCLC. Median OS was increased in patients with previously untreated, metastatic squamous NSCLC who received pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel compared with patients who received chemotherapy only (15.9 months [95% CI, 13.2not evaluable] vs 11.3 months [95% CI, 9.5-14.8]; HR, 0.64; 95% CI, 0.49-0.85;P<.001). OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, and sex.
The new FDA approval excludes patients with EGFR/ALK aberrations. Historically, the FDA approved atezolizumab for patients with metastatic NSCLC harboring EGFR or ALK abnormalities who progressed after a platinum-containing regimen and an FDA-approved targeted therapy. In the phase III OAK trial, atezolizumab reduced the risk of death by 26% compared with docetaxel and improved median OS by 4.2 months, regardless of PD-L1 status or histology (13.8 vs 9.6 months; HR, 0.74; 95% CI, 0.63-0.87;P= .0004).
The humanized monoclonal IgG1 antibody against PD-L1 is under investigation in the phase III IMpower150 and 131 trials. Results from IMpower150 suggest that median PFS was superior for patients with advanced nonsquamous NSCLC treated with the quadruplet of atezolizumab, doublet chemotherapy, and bevacizumab (Avastin) compared with bevacizumab/chemotherapy (8.3 vs. 6.8 months; HR, 0.62; 95% CI, 0.52-0.74;P<.0001). Patients derived PFS benefit from the quadruplet regardless of PD-L1 status.
In IMpower131, there is evidence that adding atezolizumab to carboplatin/nab-paclitaxel in the first line increases PFS in patients with advanced squamous NSCLC compared with the chemo-therapy doublet alone (6.3 vs 5.6 months; HR, 0.71; 95% CI, 0.60-0.85;P<.0001).
Furthermore, patients with high PD-L1 expression derived an OS benefit from the atezolizumab combination compared with chemotherapy (23.6 vs 14.1 months; HR, 0.56; 95% CI, 0.32-0.99).
Durvalumab was granted FDA approval in February 2018 for the treatment of patients with locally advanced, unresectable stage III NSCLC who did not progress following chemoradio-therapy based on PFS data from the phase III PACIFIC trial. Durvalumab improved the median PFS by 11.2 months compared with placebo (16.8 vs 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P <.0001). The 18-month PFS rate was 44.2% versus 27.0% in favor of durvalumab (P<.0001).
An update from the PACIFIC trial released in September 2018 showed that durvalumab induced a clinically meaningful improvement in OS compared with placebo in this population.4,5Patients treated with durvalumab after chemoradiotherapy demonstrated a 24-month OS rate of 66.3% (95% CI, 61.7-70.4) compared with 55.6% (95% CI, 48.9-61.8) in patients who received placebo (2-sidedP= .005).
Management of Metastatic NSCLC
There was unanimous agreement that pembrolizumab is the agent of choice in the first line for patients with PD-L1positive (tumor proportion score [TPS] ≥50%), nonsquamous disease. In certain cases, pembrolizumab plus pemetrexed/ carboplatin may also be an option in this population.
For patients with PD-L1 (TPS <50%), nonsquamous, advanced disease and no actionable mutations, the task force unanimously recommended first-line pembrolizumab plus pemetrexed/carboplatin.
The subcommittee recommended that patients with advanced nonsquamous NSCLC with at least 1 actionable mutation should receive appropriate targeted therapies.
For patients with squamous histology and PD- L1 TPS ≥50%, the task force recommended pembrolizumab monotherapy. The subcommittee also made tentative recommendations pending FDA approval of combination pembrolizumab plus nab-paclitaxel/paclitaxel for patients with advanced squamous cell disease and PD-L1 TPS <50%.
The subcommittee unanimously recommended atezolizumab, nivolumab, and pembrolizumab in the second-line setting for patients with squamous histology and PD-L1 TPS <50% who have not previously received a checkpoint inhibitor. The expert panel also recommended these drugs as third-line therapy in all patients with actionable mutations following progression after treatment with targeted agents followed by platinum-containing chemotherapy.
The subcommittee determined that patient eligibility, preference of schedule, experience of the treating physician, and drug availability/insurance coverage should be considered when choosing among atezolizumab, nivolumab, and pembrolizumab.
Herbst acknowledged that PD-L1 is the best biomarker currently available but is not without flaws. “It’s a pretty good biomarker, but it’s not the best biomarker, so to speak,” he said. “It’s subject to heterogeneity and sampling errors.”
The panel agreed that almost all patients with newly diagnosed metastatic NSCLC should undergo PD-L1 testing, including patients awaiting EGFR/ALK/ROS1 mutation testing results. Most subcommittee members preferred testing archived tissue blocks if available and obtaining fresh tissue as needed; 72% of the experts on the panel did not retest patients who were PD-L1 negative and progressed on first-line therapy.
The panel did not recommend a particular laboratory-developed test for PD-L1 analyses, concluding that Clinical Laboratory Improvement Amendmentscertified laboratories can reliably measure PD-L1 expression.
Measuring Radiographic Response
A key topic in the field has been determining how to accurately measure radiographic response in patients treated with immunotherapy. As such, immune-related response criteria were introduced, involving measurements of new lesions in the total tumor burden and 2 consecutive scans taken at least 4 weeks apart showing the appearance of new lesions, or a tumor burden increase of >20%, to confirm progressive disease.
Most subcommittee members (62%) recommended a first computed tomography (CT) scan 6 to 9 weeks after initiating ICI therapy, though few data support this practice. If the scan shows that the patient is asymptomatic or has minimal disease progression, 69% said they would continue treatment for a clinically stable patient. Thirty-nine percent of the subcommittee would repeat the CT scan after 4 weeks. If ICI treatment were to be continued beyond evidence of progression, 39% would repeat the scan. More investigation is necessary to determine whether patients with NSCLC benefit from treatment with ICIs beyond RECIST 1.1 disease progression.