Evolving Role of Immune Checkpoint Inhibitors in Lung Cancer: Combination with Chemotherapy in the First-Line Setting

Katherine Saunders, PharmD BCOP
Ambulatory Oncology Clinical Pharmacy Specialist
Georgia Cancer Center
Augusta, GA

Immune checkpoint inhibitors (ICIs) that target the programmed-death ligand 1 (PD-L1)–programmed cell death-1 (PD-1) interaction have transformed the management of many cancers. The initial role of ICIs in the management of lung cancer was in the subsequent-line setting of advanced or metastatic non-small-cell lung cancer (NSCLC) following first-line chemotherapy. Nivolumab, a PD-1 inhibitor, and atezolizumab, a PD-L1 inhibitor, received approval in this patient population regardless of PD-L1 expression on tumor tissue, whereas pembrolizumab, also a PD-1 inhibitor, was approved for patients with PD-L1 expression of 1% or greater.1-3 Though all three agents demonstrated improved overall survival (OS) when compared to docetaxel in advanced or metastatic disease as second-line therapy, clinicians and investigators aimed to determine whether moving these agents to the front-line setting in combination with platinum-based chemotherapy would be more beneficial. Several trials published in 2018 may answer this question.

Pembrolizumab Plus Chemotherapy in NSCLC
Two large randomized phase 3 trials assessing the role of pembrolizumab in combination with first-line chemotherapy in NSCLC were published in 2018. The first, KEYNOTE-189, included OS analysis of pembrolizumab plus investigators’ choice of platinum agent (cisplatin or carboplatin) plus pemetrexed for nonsquamous NSCLC.4 When the progression-free survival (PFS) data were made available in 2017, some clinicians hesitated to change practice for all patients because of a concern that the significant PFS benefit seen with triple therapy would not correlate with OS and that a change in practice would remove ICI therapy as a viable second-line option.5 However, the full OS analysis confirms the role of chemoimmunotherapy in the first-line setting. A significant OS benefit was seen in the overall population at 12 months (69.2% vs. 49.4%, hazard ratio [HR] 0.49; 95% confidence interval [CI] 0.38 to 0.64; p < .001).4 This benefit was statistically significant across all subgroups regardless of PD-L1 status or choice of platinum.4 On the basis of these results, this regimen has been approved by the U.S. Food and Drug Administration (FDA), and the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC list pembrolizumab in combination with pemetrexed and a platinum as a Category-1 preferred regimen for initial systemic therapy in metastatic or advanced nonsquamous NSCLC.6,7

Given that KEYNOTE-189 included treatment with pemetrexed, it was limited to patients with nonsquamous histology. KEYNOTE-407, published in September 2018, evaluated pembrolizumab with carboplatin and either paclitaxel or nab-paclitaxel for patients with advanced or metastatic squamous NSCLC.8 Again, a significant OS benefit was seen in the overall study population: 15.9 months with pembrolizumab plus chemotherapy versus 11.3 months with chemotherapy alone (HR 0.64; 95% CI 0.49 to 0.85; p <.001).8 All hazard ratios in the subgroup analysis favored triple therapy; however, this was not a statistically significant finding in patients 65 years of age or older (HR 0.74, 95% CI 0.51 to 1.07) and those with a PD-L1 expression of 50% or greater (HR 0.64, 95% CI 0.37 to 1.10).8 When PD-L1 was stratified by expression of less than 1% and 1% or greater, both groups were shown to benefit from chemotherapy plus pembrolizumab. These results were statistically significant.8 It is worth noting that patients with 50% or greater expression of PD-L1 can receive pembrolizumab alone as first-line therapy and may not receive additional benefit from the combination with chemotherapy.6 This study was also not powered to detect a difference in OS or PFS for subgroups. Specifically, outcomes stratified on the basis of PD-L1 expression were prespecified exploratory endpoints.8

Similar to the results of KEYNOTE-189, these results led to the designation of pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel as NCCN Category-1 preferred regimens for initial systemic therapy for squamous NSCLC.6 These are also FDA-approved combinations.7

Atezolizumab Plus Chemotherapy and Bevacizumab in NSCLC
The IMpower150 trial, published in June 2018, evaluated the role of atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.9 This trial had three arms: atezolizumab plus carboplatin and paclitaxel (ACP), bevacizumab plus carboplatin and paclitaxel (BCP), or atezolizumab plus BCP (ABCP).9 The first analysis available compared ABCP to BCP. This trial examined a new potential biomarker for response to ICI therapy, effector T-cell (Teff) gene signature.9 Teff gene signature includes expression of PD-L1, CXCL9, and IFN-? messenger RNA.9 Previous studies indicated that high Teff-gene-signature expression was a better predictor of response to atezolizumab than PD-L1 expression.2 Another notable difference with this protocol is that it allowed patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations to be enrolled if they had failed therapy with at least one tyrosine kinase inhibitor (TKI).9 PFS and OS were assessed in the wild-type (WT) population (those without EGFR or ALK mutations), as well as those patients in the WT group with high Teff gene signature.9 Median PFS was longer with ABCP when compared to BCP in the WT group (8.3 months vs. 6.8 months; HR 0.62; 95% CI 0.52 to 0.74; p < .001).9 This corresponded to an OS benefit in the same population: 19.2 months versus 14.7 months (HR, 0.78; 95% CI 0.64 to 0.96; p = .02).9 In patients with high Teff-gene-signature expression, PFS was 11.3 months versus 6.8 months (HR, 0.51; 95% CI 0.38 to 0.68; p < .001).9

Though these results demonstrate the superiority of ABCP over BCP, they do not reveal whether ACP is superior to either ABCP or BCP. The design of IMpower150 did not allow for a direct comparison of ABCP to ACP to assess the benefit of bevacizumab in this regimen.9,10 When viewed in the context of other trials showing the benefit of chemoimmunotherapy, providers may be more likely to select a three-drug rather than four-drug regimen to avoid additional adverse events and unnecessary healthcare costs. The four-drug regimen has been added as a Category-1 recommendation in NCCN guidelines for advanced or metastatic nonsquamous NSCLC and was recently approved by the FDA.6,11

Atezolizumab Plus Chemotherapy in Small-Cell Lung Cancer (SCLC)
Perhaps most encouraging of the chemoimmunotherapy trials was the IMpower133 study. This trial marks the first improvement in OS for patients with extensive-stage SCLC in decades. When compared to carboplatin and etoposide, the addition of atezolizumab lengthened OS, with a median OS of 12.3 months in the atezolizumab plus chemotherapy group versus 10.3 months in the chemotherapy group (HR 0.70; 95% CI 0.54 to 0.91, p = .007).12 In a patient population with such poor prognosis, a 2-month benefit could be meaningful to patients. However, the value of adding a third drug with potential for immune-mediated side effects for a 2-month survival benefit needs to be discussed openly with providers and patients.

Conclusions and Future Directions
Several trials published in 2018 confirm the role of immunotherapy combined with chemotherapy as first-line treatment for lung cancer. However, several questions have yet to be answered:

  1. Would some patients benefit more from sequential administration of chemotherapy followed by immunotherapy than from chemotherapy and immunotherapy administered concurrently?
  2. Is PD-L1 expression the best biomarker to predict response to ICIs, or should we incorporate other markers such as Teff or tumor mutational burden as studied in CheckMate 22713 in the workup for NSCLC?
  3. What financial burden will patients, institutions, and the healthcare system overall experience with increasing ICI-combination treatments in the first-line setting?
  4. What is the optimal second-line treatment for NSCLC following ICI therapy?

As these and other questions are answered, the landscape of NSCLC and SCLC treatment will continue to evolve.


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