Immunotherapy, Targeted Therapy Enter Localized Setting in Non–Small Cell Lung Cancer

Benjamin P. Levy, MD

Immunotherapies and targeted therapies therapies have made a significant impact on the treatment of patients with advanced non– small cell lung cancer (NSCLC), with approvals of numerous new agents over the past decade. More recently, investigators are considering the possible use for many of these agents in earlier disease settings with curative intent.

In a presentation at the 17th Annual New York Lung Cancers Symposium®, Benjamin P. Levy, MD, discussed the treatment of patients with stage I to stage III NSCLC, including with agents that are approved for use in advanced stages. Levy is the clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC.

In the phase 3 ADAURA trial (NCT02511106), investigators did not use immunotherapy but instead treated patients with the EGFR tyrosine kinase inhibitor osimertinib (Tagrisso) in patients with completely resected stage IB/II/IIIA NSCLC harboring an exon 19 deletion or L858R alteration. Patients were randomly assigned to receive osimertinib 80 mg/d (n = 339) or placebo daily (n = 343) until 3-year recurrence or discontinuation.

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-year and 3-year DFS rates, and safety.¹

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) (TABLE 1¹). 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. There were 22 patients in the investigational arm who 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. These findings led to the FDA approval of an adjuvant indication for osimertinib in December 2020.

Similarly, in the phase 3 IMpower010 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).^2,3

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.

The FDA approved atezolizumab as an adjuvant therapy following resection and platinum-based chemotherapy for patients with stage II to IIIA NSCLC whose tumors have positive PD-L1 expression on tumor cells in October 2021.

Another study assessed the use of pembrolizumab (Keytruda) as an adjuvant therapy for patients with completely resected stage IB to IIIA NSCLC. At a median 35.6 months, the phase 3 PEARLS/KEYNOTE-091 trial (NCT02504372) demonstrated a median DFS of 53.6 months (95% CI, 39.2-NR) with pembrolizumab compared with 42.0 months (95% CI, 31.3-NR) in the placebo arm (HR, 0.76; 95% CI, 0.63-0.91; P = .0014). Among patients with a PD-L1 expression by tumor proportion score of 50% or greater, the median DFS was not reached in either arm (HR, 0.82; 95% CI 0.57-1.18; P = .14).⁴

In June 2022, the FDA accepted a supplemental biologics license application for pembrolizumab as an adjuvant treatment for patients with stage IB, II, or IIIA NSCLC following complete surgical resection based on the results of the KEYNOTE-091 trial. The Prescription Drug User Fee Act target date for a decision on the application is January 29, 2023.⁵

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 receive either durvalumab at 10 mg/kg every 2 weeks for up to 12 months (n = 476) or placebo at the same dosing schedule (n = 237). The primary end points were PFS and OS.⁶

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 (TABLE 2⁷). 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.⁷

_REFERENCES:

_{1. 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}

_{2. Felip E, Altorki N, Zhou C, et al; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5}

_{3. 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}

_{4. O’Brien M, Paz-Ares L, Marreaud S, et al; EORTC-1416- LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/ KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6}

_{5. FDA accepts application for Merck’s KEYTRUDA (pembrolizumab) as adjuvant therapy for stage IB (≥ 4 centimeters)-IIIA non-small cell lung cancer following complete surgical resection. News release. Merck. June 13, 2022. Accessed November 18, 2022. https://bit.ly/3OgxPe2}

_{6. 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. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.0130}

_{7. 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. doi:10.1001/jamanetworkopen.2022.15589}