Neoadjuvant immunotherapy plus chemotherapy in early-stage NSCLC

Presentation, treatment and response
A 52-year-old male former smoker presented with cough and haemopty­sis in September 2022. Upon exam­ination, he was not dyspnoeic and did not require supplemental oxygen. He had type 2 diabetes mellitus, hyper­tension and alcoholic liver cirrhosis.

Further assessments confirmed squamous-cell non-small-cell lung cancer (NSCLC) with no actionable mutations and a PD-L1 score of <1 percent. PET-CT scan showed a 6.7 cm mass at the right lower lung lobe, with invasion into the right bron­chus (ie, T3). (Figure 1A) The baseline fluorine-18-fluorodeoxy-D-glucose (FDG) maximum uptake value was 11. There was also mild FDG uptake in the ipsilateral subcarinal lymph nodes (LNs), indicative of possible LN metas­tasis (ie, N2). He was assessed to have clinical stage IIIB disease (T3N2M0) based on the latest 8^th edition of the American Joint Committee on Cancer (AJCC) staging criteria.¹ According to the earlier 7^th edition of AJCC crite­ria, the patient had stage IIIA disease (T2bN2M0).²

The patient was relatively well and had a baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. His disease was as­sessed as potentially resectable, lead­ing to a recommendation of three cy­cles of neoadjuvant immunotherapy plus platinum-doublet chemotherapy to facilitate preoperative downstag­ing.³

In November 2022, the patient started treatment with same-day intra­venous (IV) infusions of nivolumab at 360 mg Q3W, paclitaxel at 175 mg/m², and carboplatin at dose [area under the curve (AUC) 5 x (creatinine clear­ance [CrCl] mL/min + 25)] mg Q3W. With the exception of paclitaxel-relat­ed grade 1 sensory neuropathy, which resolved spontaneously, the patient tolerated his treatment well and com­pleted the recommended three cycles in December 2022, with no dose re­ductions or treatment interruptions.

In February 2023, repeat PET-CT showed good tumour response, with the right lower lung lobe mass reduc­ing to 2.7 cm. (Figure 1B) There was also no residual FDG uptake in either the primary lung mass or the subca­rinal LNs. Endobronchial ultrasound confirmed negative results in the LNs sampled. The patient’s symptoms also resolved and his PS improved to 0. He was recommended to proceed with surgery.

Lobectomy of the right lower and middle lobes with lymph node dissec­tion was performed in April 2023. Sub­sequent pathology report confirmed major pathological response after neo­adjuvant therapy, with margin-negative resection and only N1 disease. Based on these findings, no further adjuvant therapy was recommended. Last seen in May 2023, the patient remained well. He will be regularly monitored for signs of disease progression.

Discussion
Surgery remains the best cura­tive option for most patients with early-stage NSCLC, with neoadjuvant systemic therapy recommended for tumour downstaging and increasing chances of complete resection. In some cases with N2 disease, surgeons may resort to neoadjuvant chemo-radiotherapy, as surgical outcomes with neoadjuvant chemotherapy alone are often unsatisfactory.^3,4

Although several options are avail­able, neoadjuvant chemotherapy only improves 5-year recurrence-free survival and overall survival (OS) by approximately 5 percent vs surgery alone.^3,5 Neoadjuvant chemotherapy is also associated with minimal patholog­ical complete response (pCR), a sur­rogate endpoint for survival in clinical trials.^6,7 The alternative of neoadjuvant chemoradiotherapy achieves higher rates of pCR and negative mediastinal LNs, but does not significantly improve OS and is associated with excessive postoperative mortality.^3,8

Nivolumab (in combination with platinum-doublet chemotherapy) is the first and currently only immune checkpoint inhibitor (ICI) recommend­ed as neoadjuvant treatment for adults with early-stage resectable NSCLC in the latest version of National Cancer Comprehensive Network’s (NCCN) clinical practice guidelines. The guide­lines also strongly suggest this combination for patients with tumours ≥4 cm or node-positive disease and no contraindications to ICIs.^3,9

The NCCN recommendation is based on results of the open-label, randomized phase III CheckMate 816 trial in 358 patients with resectable NSCLC (stage IB–IIIA, based on the earlier 7^th edition of AJCC staging), who received either the recommended three cycles of neoadjuvant nivolumab plus platinum-doublet chemothera­py or platinum-based chemotherapy alone, followed by resection. The pri­mary endpoint of event-free survival (EFS) was longer with nivolumab plus chemotherapy vs chemotherapy alone (median, 31.6 months vs 20.8 months; hazard ratio [HR], 0.63; 97.38 percent confidence interval [CI], 0.43–0.91; p=0.005; minimum follow-up, 21 months). pCR rates (ie, 0 percent vi­able tumour cells in both primary tu­mour [lung] and sampled LNs) also improved in the nivolumab vs chemo­therapy alone group (24.0 percent vs 2.2 percent; odds ratio, 13.94; 99 per­cent CI, 3.49–55.75; p<0.001). Impor­tantly, pCR rates were improved with the addition of nivolumab across all subgroups, including any tumour his­tology type, disease stage at baseline, and PD-L1 expression level.¹⁰

Higher incidences of major patho­logical response, like that achieved by our patient, were seen with nivolumab plus chemotherapy vs chemothera­py alone among patients who under­went resection and among those with lymph-node involvement on imaging at baseline as well as when response was assessed in the primary tumour only.¹⁰

Surgery cancellation rate was not negatively affected by addition of nivolumab to chemotherapy, with de­finitive surgery rates of 83 percent vs 75 percent in the nivolumab plus che­motherapy vs chemotherapy alone group. Addition of nivolumab also did not impede the feasibility and timing of surgery, or the extent or completeness of resection vs chemotherapy alone, nor did it increase surgical complica­tions vs chemotherapy alone. More patients in the nivolumab plus chemo­therapy vs chemotherapy alone group received less invasive surgery, with lo­bectomy performed in 77 percent vs 61 percent and pneumonectomy in 17 percent vs 25 percent of patients, respectively. In addition, there was a higher complete resection (R0) rate among patients treated with nivolum­ab plus chemotherapy vs chemother­apy alone (83 percent vs 78 percent).¹¹

Nivolumab plus chemotherapy was generally well tolerated and did not in­crease the incidence of adverse events (AEs) vs chemotherapy alone. Rates of grade 3/4 treatment-related AEs were similar in both groups (33.5 percent vs 36.9 percent). The most common grade 3/4 treatment-related AEs were neutropenia (8.5 percent vs 11.9 per­cent) and decreased neutrophil count (7.4 percent vs 10.8 percent). As im­munotherapy was only given for three cycles, the incidence of immune-mediated AEs was low, and events were mainly of grade 1/2. The most common immune-mediated AE of any grade with nivolumab plus chemother­apy was rash (8.5 percent).¹⁰

CheckMate 816 results are consis­tent with the experience of our patient, who had squamous-cell T3N2M0 dis­ease with a PD-L1 score of <1 percent prior to neoadjuvant therapy (or T2b­N2M0, stage IIIA as per the 7^th edition of AJCC staging used in CheckMate 816) and achieved a major patholog­ical response with margin-negative resection and N1 disease after three cycles of neoadjuvant nivolumab plus platinum-doublet chemothera­py.^2,10 Tumour downstaging is sug­gestive of improved prognosis and an encouraging result from surgeons’ perspective.^3,4

In summary, CheckMate 816 and our patient’s case support use of neoadjuvant nivolumab plus che­motherapy in early-stage resectable NSCLC, regardless of histology type and PD-L1 expression. As per NCCN recommendations, the CheckMate 816 regimen should be strongly con­sidered for patients with tumours ≥4 cm or node-positive disease with no contraindications to ICIs. In particu­lar, patients with potentially resectable stage III disease ought to be evaluated for neoadjuvant therapy as they have a poorer postsurgical prognosis without it.^3,10,12