Checkpoint Inhibitor Challenges Warrant Consideration for a Targeted Approach in NSCLC

In treating patients with locally advanced non–small cell lung cancer, one must consider multiple factors when deciding whether to treat them with immunotherapy or a targeted approach, even though the optimal treatment sequence has yet to be definitively established.

Benjamin P. Levy, MD

In treating patients with locally advanced non–small cell lung cancer (NSCLC), one must consider multiple factors when deciding whether to treat them with immunotherapy or a targeted approach, even though the optimal treatment sequence has yet to be definitively established, according to Benjamin P. Levy, MD.1

“Consolidation immunotherapy remains the standard of care for patients with locally advanced disease status post concurrent chemoradiation,” Levy, the clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC, said during a presentation during the 17th Annual New York Lung Cancers Symposium® in New York, New York. “[However], consideration must be given to deliver genotype-directed therapies, at least for patients harboring ALK and EGFR [alterations], in this setting instead of immunotherapy.”

Levy cited the lackluster efficacy of immunotherapy in NSCLC for patients whose disease harbors genomic alterations. Retrospective data of patients with advanced NSCLC with at least 1 oncogenic driver alteration who received monotherapy with an immune checkpoint inhibitor suggested that patients with actionable tumor alterations should receive targeted therapies and chemotherapy before immunotherapy.2

According to the study, patients in the overall population (N = 551) experienced an overall response rate (ORR) of 19%, a median progression-free survival (PFS) of 2.8 months, and a median overall survival (OS) of 13.3 months following treatment with an immune checkpoint inhibitor. More specifically, patients with KRAS alterations (n = 271) achieved an ORR of 26%, a median PFS of 3.2 months, and a median OS of 13.5 months. Patients with EGFR mutations (n = 125) displayed even worse outcomes, with an ORR of 12%, a median PFS of 2.1 months, and a median OS of 10.0 months.

A phase 2 trial (NCT02879994) illustrated some potential drawbacks with the PD-1 inhibitor pembrolizumab (Keytruda) for patients with NSCLC harboring genomic alterations. The trial enrolled patients with advanced NSCLC and a PD-L1 status of at least 1% positivity harboring an EGFR alteration who had not been treated with a TKI. Patients received pembrolizumab 200 mg every 3 weeks until disease progression or a total of 35 infusions. Following completion of pembrolizumab, patients moved on to treatment with an EGFR TKI.3

The patients who received a subsequent EGFR TKI (n = 7) were shown to be at risk for potentially fatal pneumonitis. One patient experienced grade 3 to 5 pneumonia when treated with an EGFR TKI after pembrolizumab. There was also 1 case of grade 3 to 5 transaminitis, and 1 case of grade 3 to 5 gastrointestinal diarrhea following this treatment sequence.

Similarly, a retrospective study evaluated 126 patients with EGFR-mutant NSCLC treated with PD-(L)1 blockade and EGFR TKIs, regardless of drug or sequence of administration. Six of these patients experienced a sever immune-related adverse effect (AE) after treatment with sequential PD-(L)1 blockade followed later by osimertinib (Tagrisso). Most of these patients with a severe immune-related AE (n = 4) experienced grade 3 pneumonitis, 3 of whom needed to be hospitalized.4

Other trials have evaluated an earlier use of targeted therapy in the localized setting. For example, in the phase 3 ADAURA trial (NCT02511106), investigators did not use immunotherapy but instead treated patients with the EGFR TKI osimertinib in patients with completely resected stage IB/III/IIIA NSCLC harboring an exon 19 deletion or L858R alteration. Patients were randomly assigned to receive osimertinib 80 mg daily (n = 339) or placebo daily (n = 343) until 3-year recurrence or discontinuation; adjuvant chemotherapy was allowed.

The primary end point was investigator-assessed disease-free survival (DFS) in those with stage II/IIIA disease. Secondary end points included DFS in the overall population, 2- and 3-year DFS rates, and safety.5

Findings showed that patients with stage II/IIIA disease in the investigational arm (n = 233) experienced a median DFS of 65.8 months (95% CI, 54.4-not calculated [NC]) compared with 21.9 months (95% CI, 16.6-27.5) in the 237-patient control arm (HR, 0.23; 95% CI, 0.18-0.30). The overall median DFS was 65.8 months (95% CI, 61.7-NC) vs 28.1 months (95% CI, 22.1-35.0), respectively (HR, 0.27; 95% CI, 0.21-0.34). The median follow-up in the osimertinib arm was 44.2 months (range, 0-67).

Additional data from the trial exhibited that osimertinib also improved central nervous system (CNS) DFS rates compared with placebo for patients with stage II/IIIA NSCLC. Twenty-two patients in the investigational arm experienced a CNS DFS event compared with 41 in the control arm. The median CNS DFS was not reached (NR; 95% CI, 65.8-NC) vs NR (95% CI, NC-NC), respectively (HR, 0.24; 95% CI, 0.14-0.42). The probability of CNS recurrence at 36 months was 2% (95% CI, 0.9%-5.0%) compared with 13% (95% CI, 8.5%-18.5%), respectively.

Similarly, in the phase 3 IMPOWER 010 trial (NCT02486718), investigators compared the safety and efficacy of the PD-L1 inhibitor atezolizumab (Tecentriq) with best supportive care (BSC) among patients with stage IB to IIIA NSCLC following chemotherapy and resection. At a median follow-up of 32 months, the atezolizumab arm had superior median DFS vs BSC among patients with stage II to IIIA disease and a PD-L1 expression of at least 1% (HR, 0.66; 95% CI, 0.50-0.88; P = .0039), all randomized patients with stage II to stage IIIA disease (HR, 0.79; 95% CI, 0.64-0.96; P = .0205), and randomized patients with stage IB to IIIA disease (HR, 0.81; 95% CI, 0.67-0.99; P = .0395).6,7

OS data were immature at the time of his presentation, Levy noted. However, a subgroup analysis of OS in patients with PD-L1 positivity of at least 1% and stage II to IIIA disease found that patients with an EGFR mutation performed better in terms of OS when treated with atezolizumab vs BSC (HR, 0.77; 95% CI, 0.22-2.67). The median follow-up in this analysis was 46 months.

Levy then focused on how clinicians can use the information currently available to best decide the treatment sequence of immunotherapy vs targeted agents in locally advanced NSCLC.

In the phase 3 PACIFIC trial (NCT02125461), investigators compared durvalumab (Imfinzi) with placebo in adult patients with unresectable, stage III NSCLC irrespective of PD-L1 status. Patients were randomly assigned 2:1 to received either durvalumab at 10 mg/kg every 2 weeks for up 12 months (n = 476) or placebo at the same dosing schedule (n = 237). The primary end points were PFS and OS.8

In this case, durvalumab was superior to placebo in terms of median PFS, at 17.2 months (95% CI, 13.1-23.9) vs 5.6 months (95% CI, 4.6-7.7), respectively (HR, 0.51; 95% CI, 0.41-0.63). The median OS was not NR (95% CI, 34.7-NR) with durvalumab vs 28.7 months (95% CI, 22.9-NR) with placebo (HR, 0.68; 99.73% CI, 0.469-0.997; P = .00251).

In a cohort of PACIFIC, results showed that driver oncogene variations had a significant impact on the efficacy of durvalumab. Patients with driver variations experienced an inferior PFS (log-rank P < .001) and OS (log-rank P = .24) compared with those who had nondriver variations.9

While Levy said that many questions remain in terms of defining the role of immunotherapy vs targeted therapy in this patient population, some trials are underway to answer them. The ongoing phase 3 LAURA trial (NCT03521154) is comparing osimertinib as maintenance therapy with placebo after definitive chemoradiation in patients with unresectable, EGFR-mutant stage III NSCLC. After chemoradiation, patients will be randomly assigned 2:1 to receive with osimertinib 80 mg daily or placebo until disease progression. The primary end point is PFS, and secondary end points include CNS PFS, OS, and safety.10

There are also ongoing clinical trials examining the role of ctDNA and minimal residual disease as prognostic biomarkers in the space, said Levy.

“Immunotherapy may actually be doing harm in these patients, given the importance of delivering targeted therapy if patients progress,” Levy said. “LAURA will hopefully clarify this role, at least in the EGFR space.”


  1. Levy BP. Oncogene-driven, locally advanced NSCLC: immunotherapy or targeted therapy? Presented at: 17th Annual New York Lung Cancers Symposium; November 12, 2021; New York, New York.
  2. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328. doi:10.1093/annonc/mdz167
  3. Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13(8):1138-1145. doi:10.1016/j.jtho.2018.03.035
  4. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077
  5. Tsuboi M, Wu Y, Grohe C, et al. Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): updated results from ADAURA. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089
  6. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial [published correction appears in Lancet. 2021 Sep 23.]. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
  7. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500
  8. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer [published correction appears in J Clin Oncol. 2022 Jun 10;40(17):1965]. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
  9. Liu Y, Zhang Z, Rinsurongkawong W, et al. Association of driver oncogene variations with outcomes in patients with locally advanced non-small cell lung cancer treated with chemoradiation and consolidative durvalumab. JAMA Netw Open. 2022;5(6):e2215589. Published 2022 Jun 1. doi:10.1001/jamanetworkopen.2022.15589
  10. A global study to assess the effects of osimertinib following chemoradiation in patients with stage iii unresectable non-small cell lung cancer (LAURA). updated October 21, 2022. Accessed November 14, 2022.
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