Neoadjuvant PD-1 ICI plus chemotherapy in early-stage resectable NSCLC

Presentation, treatment and response
A 79-year-old male chronic drinker and smoker, with a 60 pack-years smok­ing history, presented with an incidental finding of a right middle lobe lung mass following a chest CT scan for aorta-related pathology in June 2023. He had hypertension, mild chronic obstructive pulmonary disease (COPD), chronic kid­ney disease (CKD) and abdominal aortic aneurysm (AAA) with known celiac and inferior mesenteric artery (IMA) stenosis.

The hypermetabolic lung mass mea­sured 7.3 x 6.8 cm and had a maximum standardized uptake value (SUV_max) of 15.9. (Figure 1A) The patient’s ipsilat­eral paratracheal, hilar and subcarinal lymph nodes (LNs) were hypermetabolic, suggesting stage III disease (stage IIIB, T4N2M0 disease based on the 8^th edition of the AJCC staging criteria).^1,2 CT-guided biopsy confirmed squamous-cell non-small-cell lung cancer (NSCLC). Molec­ular testing confirmed EGFR-negative disease with insufficient tissue for further ALK and PD-L1 expression level testing.

The patient was relatively fit, with a baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. His disease was assessed to be re­sectable, and he was recommended neo­adjuvant immunotherapy with nivolumab (intravenous [IV], 360 mg Q3W) plus pa­clitaxel and carboplatin to facilitate pre­operative tumour shrinkage, which was commenced on 30 August 2023.^1,3

The patient completed neoadjuvant therapy on 11 October 2023. He tolerated treatment well, with no dose reductions or treatment interruptions. Follow-up PET-CT scan showed substantial gross re­duction of the lung mass to 7.0 x 3.5 cm. SUV_max declined to 4.3. (Figure 1B)

Surgery was performed on 24 No­vember 2023. Dense adhesions around the right middle lobe (superior pulmonary vein area) were discovered intraoperative­ly, which resulted in moderate bleeding, necessitating conversion from minimally invasive surgery to open thoracotomy. Middle lobectomy of the right lung and right upper lobe anterior segmentectomy were performed, as the tumour crossed the fissure. The operation took 3.5 hours and was otherwise uneventful, with a total blood loss of 450 mL and no postopera­tive air leaks.

The patient experienced some postoperative complications, including chest infection, sepsis, atrial fibrillation, and COPD exacerbation. These were adequately managed and controlled with medications (ie, airway puffs with budesonide/formoterol, prednisolone, in­travenous levoflaxacin, and amiodarone). He was discharged from hospital after 7 days.

Postoperative pathology report con­firmed that the patient achieved patho­logical complete response (pCR). After discussing succeeding treatment options, the patient and his family decided to have no adjuvant therapy. The patient was last seen on 11 April 2024 and remained well. (Figure 1C) He will be regularly monitored for signs of disease progression.

Discussion
Neoadjuvant therapy is an important component of resectable NSCLC man­agement, which is intended to facilitate subsequent surgery. Its successful im­plementation requires concerted efforts of a multidisciplinary team consisting of oncologists, surgeons, radiologists and molecular pathologists.¹

From a surgical perspective, the goal of neoadjuvant immunotherapy in NSCLC management is to improve tumour resect­ability, treat any micrometastatic disease, and prime the patient’s immune system against recurrence while a large-volume tumour and tumour antigens are still pres­ent.^1,4-6 Neoadjuvant therapy is not intend­ed to convert unresectable tumours to resectable ones, and initial resectability is one of the key eligibility criteria for receiv­ing neoadjuvant nivolumab.^1,3,4

The open-label, randomized phase III CheckMate 816 trial in 358 patients with resectable NSCLC compared use of three neoadjuvant cycles of nivolumab plus platinum-doublet chemotherapy or che­motherapy alone, followed by resection. Patients with known EGFR mutations or ALK translocation were excluded.⁴

Patients in the nivolumab vs chemo­therapy alone group had higher rates of minimally invasive surgery (30 vs 22 per­cent), lower rates of conversion from min­imally invasive to open surgery (11 vs 16 percent), higher lobectomy rates (77 vs 61 percent), lower pneumonectomy rates (17 vs 25 percent), and higher R0 resec­tion rates (83 vs 78 percent).⁷

Most patients in both treatment arms had surgery within the protocol-specified time window. No increase in median du­ration of surgery (184 vs 217 minutes) and length of hospitalization (10.0 vs 10.0 days) was found with the addition of nivolumab to neoadjuvant chemothera­py vs chemotherapy alone. Neoadjuvant nivolumab was not associated with an in­creased incidence of surgery-related AEs and did not impede the feasibility and timing of surgery, or the extent or com­pleteness of resection vs chemotherapy alone.⁷

Although our patient required tho­racotomy instead of minimally invasive surgery after intraoperative discovery of adhesions, it is difficult to ascertain whether those were the result of neoad­juvant treatment with nivolumab. In our clinical experience, surgery-complicating adhesions are strongly associated with neoadjuvant chemoradiotherapy, while neoadjuvant immunotherapy may not have the same effect.⁸

Of note, some patients who receive neoadjuvant ICI therapy may exhibit a phenomenon of “nodal immune flare”, which manifests as an unusual radiologi­cal appearance of LN enlargement. While this finding mimics disease progression, pathological evaluation may show in­creased immune cell infiltration and re­gression in cancer. Therefore, invasive pathological evaluation of LNs that are deemed suspicious by radiological crite­ria may be necessary for establishing or ruling out true progression.⁹

Since neoadjuvant chemotherapy of­fers minimal pCR rates and only improves 5-year recurrence-free survival and over­all survival (OS) rates by approximately 5 percent vs surgery alone, neoadjuvant immunotherapy offers a much-needed alternative.^8,10,11

Nivolumab (in combination with platinum-doublet chemotherapy) is the first immune checkpoint inhibitor (ICI) rec­ommended for neoadjuvant treatment of patients with early-stage resectable NS­CLC. On the basis of CheckMate 816 re­sults, international guidelines recommend strong consideration of neoadjuvant nivolumab plus chemotherapy for patients with stage IB (≥4 cm) to IIIA NSCLC with­out EGFR or ALK aberrations.^1,3,4

The addition of nivolumab to che­motherapy significantly improved the pri­mary endpoint of pCR rate in the overall CheckMate 816 population, regardless of extent of resection (24.0 vs 2.2 per­cent; odds ratio, 13.94; 99 percent CI, 3.49–55.75; p<0.001). Importantly, this pCR benefit was observed across all key subgroups, irrespective of disease stage, tumour PD-L1 expression level and histo­logic type.⁴

The trial also achieved its other pri­mary endpoint of EFS, which was lon­ger with nivolumab plus chemotherapy vs chemotherapy alone.⁴ In the 4-year update from CheckMate 816, median EFS was 43.8 months with nivolum­ab plus chemotherapy vs 18.4 months with chemotherapy alone (hazard ra­tio [HR], 0.66; 95 percent confidence interval [CI], 0.49–0.90). The respec­tive 48-month EFS rates were 49 and 38 percent.¹²

CheckMate 816 investigators not­ed the strong association between pCR and clinical benefit and suggested that pCR may be used as an early indicator of therapeutic efficacy in resectable NS­CLC.⁴ In the 3-year update of CheckMate 816, among patients with a pCR, median event-free survival (EFS) was not reached in both treatment groups. In patients with­out a pCR, median EFS was 27.8 months in the nivolumab group vs 20.8 months with chemotherapy alone (HR, 0.89; 95 percent CI, 0.64–1.22). (Figure 2) Similar results were observed in terms of over­all survival (OS). These results show that pCR was associated with both improved EFS and OS in patients treated with neo­adjuvant nivolumab plus chemotherapy as well as those treated with chemother­apy alone.¹³

In the 4-year update from Check­Mate 816, although median OS was not reached in either arm, neoadjuvant nivolumab plus chemotherapy demon­strated a clinically important OS im­provement trend vs chemotherapy alone (HR, 0.71; 98.36 percent CI, 0.47–1.07; p=0.0451), which, however, did not meet significance boundary. The addition of nivolumab to chemotherapy improved lung cancer–specific survival vs chemo­therapy alone (unstratified HR, 0.62; 95 percent CI, 0.41–0.93).¹²

In terms of overall safety, the inci­dence of grade 3/4 treatment-related AEs (TRAEs) was generally similar between the nivolumab plus chemotherapy and chemotherapy alone groups (33.5 and 36.9 percent). The most common grade 3/4 TRAEs were neutropenia (8.5 vs 11.9 percent) and decreased neutrophil count (7.4 vs 10.8 percent). Importantly, 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).⁴ The safety profile of neoadjuvant nivolumab plus chemotherapy remained consistent with previous reports in the latest 4-year update.¹²

Conclusion
The present case and results of the first positive phase III trial of immunotherapy-based combination neo­adjuvant therapy support use of neoad­juvant nivolumab in combination with platinum-based chemotherapy in patients with early-stage resectable NSCLC and no actionable mutations.^1,4,7,12

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