Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer

Abstract

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.

Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20).

Results: With a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor (EGFR), 2 KRAS, 1 ERBB2, and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)-NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors.

Conclusions: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC.

Keywords: Immunotherapy; Ipilimumab; Lung Cancer; Nivolumab; Recurrence.

Figure 1. Treatment failure was defined as any progression of primary lung cancer in patients without surgery, radiographic and/or biopsy proven lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Lung cancer recurrence/progression-free survival was defined as no evidence of progression and/or recurrence from the primary lung cancer at last radiographic scan since randomization. n, number.

Figure 2. Patients with tumors harboring actionable genomic alterations (AGAs, n=12) were compared to the non-AGAs + NP SCC group, which included profiled tumors without AGAs and non-profiled squamous cell carcinomas (n=20); Tumor histology is at baseline. *Molecular profiling methods included next-generation sequencing (NGS DNA panel and/or NGS RNA fusion panel, when available), and/or cytogenetic studies (when available), and/or circulating cell-free DNA (ccfDNA) (when available) via liquid biopsy. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; n, number; NP SCC, non-profiled squamous cell carcinomas.

Figure 3. (A) Violin plot showing the pathological response in the resected tumor specimens from patients who underwent curative-intent surgery on trial in AGAs group (patients with tumors harboring an actionable genomic alterations, n=9) versus the non-AGAs+NP SCC group (patients with genomic profiling without AGAs or with non-profiled squamous cell carcinomas, n=19). The dds ratio of MPR was calculated in univariable logistic regression comparing the odds of achieving MPR in non-AGAs+NP SCC group with AGAs group. The dashed line indicates the median; the dotted lines indicate the lower quartile and upper quartile values; the top and bottom of the violin plots indicate the minima and maxima. (B) Kaplan-Meier curves of treatment failure-free survival probability for patients in the non-AGAs+NP SCC (n=20) and AGAs (n=12) groups. The 95% CIs are shown in parentheses by each treatment failure-free rate at 36, 48, and 60 months. The median time to TF with 95% CI was estimated using Kaplan-Meier method. Treatment failure was defined as any progression of primary lung cancer in patients without surgery, radiographic and/or biopsy-proven lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer, since randomization. AGAs, actionable genomic alterations; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; MPR; major pathologic response (residual viable tumor ≤ 10% in the resected tumor specimen); NE, not evaluable; NP SCC, non-profiled squamous cell carcinomas; TF, treatment failure.

Figure 4. Forest plot showing the treatment failure HR for each variable. The HR from the univariable Cox proportional hazard regression estimates the risk of TF in the interest group relative to the risk in the reference group. Treatment failure was defined as any progression of primary lung cancer in patients without surgery, radiographic and/or biopsy-proven lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer, since randomization. * Data collected at time of surgery in resected tumors in patients who underwent surgery on trial (n=28), three patients in AGAs and one patient in non-AGAs+NP SCC did not undergo surgery; time from surgery until treatment failure was used. ** Pretreatment tumor PD-L1 expression status (n=21) on available samples by clone 28-8, Abcam; the PD-L1 expression status of three patients in AGAs and eight patients in non-AGAs+NP SCC were unavailable. § Tumor histology at baseline. AGAs, patients with tumors harboring an actionable genomic alteration; MPR, major pathologic response (≤ 10% residual viable tumor in the resected tumor specimen); non-AGAs+NP SCC, patients with molecular profiling without AGAs or non-profiled squamous cell carcinomas; PD-L1, programmed death-ligand 1; TF, treatment failure; HR: hazard ratio.

Figure 5. Swimmer plot showing duration of time free from treatment failure (blue) and time since treatment failure (red) in patients with tumors without an actionable genomic alteration (AGAs) or a non-profiled squamous cell carcinomas (non-AGAs+NP SCC, patients 1–20) and patients with tumor harboring an AGA (AGAs, patients 21–32). Chemotherapy, ICI-based therapy, and targeted therapy were started after treatment failure (TF). Non-profiled adenocarcinomas (n=12) are not included. Type of treatments each patient received are displayed chronologically based on time since randomization. Patient 23 had surgery off-trial. Patient 24 did not have disease progression after neoadjuvant therapy, was offered curative-intent surgery but declined. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor.