Case Presentation: Early-Stage Non-Small Cell Lung Cancer

65-year old female, former tobacco user (30 pk-years; quit 10 years prior to presentation) presents with cough and mild increase in DOE. Physical exam is unremarkable, CXR and subsequent CT chest demonstrate a 3 cm L lung mass but appear otherwise negative for abnormalities. PET confirms uptake in the mass and in a non-enlarged L peri-hilar LN and there is no evidence of extra-thoracic tumor. FOB/EBUS within a week of initial presentation proves positive for squamous cell carcinoma in both the primary and hilar LN. There is no evidence of N2 involvement, MRI brain is negative, and PD-L1 is pending at the time of initial evaluation. She is accompanied by her spouse and oldest daughter.

Question #1: Is there a role for chemotherapy in this patient’s case, either pre- or post-operatively? 

Question # 2: Do you embark upon a specific treatment recommendation or wait for PD-L1 results?

Question # 3: Does NGS play a significant role in therapeutic decision-making in this situation?

The LACE meta-analysis clearly demonstrated a DFS and OS advantage for 4 cycles of platinum-based adjuvant chemotherapy post-resection in patients with node positive disease.¹  In individual trials such as ANITA² and BR10³, the absolute survival benefit at 5 years ranged from 5% to 15%. Ideally, it is important to know the PD-L1 status before embarking on a treatment plan. While neoadjuvant therapy can yield a DFS benefit regardless of PD-L1 status, it is much more pronounced in those whose tumors are PD-L1 positive, especially > 50%, so one might be a bit more inclined to consider neoadjuvant chemo-immunotherapy in patients whose tumors are PD-L1 positive. Finally, the role of NGS is limited in squamous cell histology. The likelihood of tumor harboring either an EGFR mutation or an ALK fusion is quite low. On the other hand, in patients with non-squamous NSCLC, the incidence is much higher, particularly in those who never smoked. If we know a tumor harbors an actionable oncogenic driver pre-op, we would be disinclined to consider neoadjuvant or peri-adjuvant chemoimmunotherapy and instead proceed with adjuvant chemotherapy or TKI, or both.^{4, 5}

The patient’s tumor returned PD-L1 positive at 80%. We opted to proceed with neoadjuvant cisplatin, pemetrexed, and pembrolizumab for 4 cycles based on the positive results of the KN671 trial,^6,7 which demonstrated both a DFS (HR 0.58; CI, 0.46-0.72; P < .00001) and OS benefit compared to neoadjuvant chemotherapy alone. The 2-year DFS was 62.4% vs 40.6%, and for OS, the HR was 0.72 with p value of .00517, median NR vs 52.4 months with separation in the OS curves largely occurring beyond 2 years. The HR for EFS was 0.60 in N1 resected cancers, and in those with PD-L1 > 50%, the HR was 0.42. The HR for OS followed the same pattern, 0.74 for N1 and 0.55 for PD-L1 > 50%. The mPR rate was 30.2% for all enrollees on the investigational arm vs 11.0% for the control arm.

Beyond the positive results of KN671, there are several additional theoretical advantages for neo- or peri-adjuvant chemoimmunotherapy⁸:

•   This approach is better tolerated pre-op. 

•   IOs may be more effective with the tumor in situ rather than post resection.

•   Less time for clonal evolution – more homogenous tumors, potentially more sensitive to the effects of both chemotherapy and checkpoint inhibitors.

•   Opportunity for a lesser lung resection.

•   Capacity to assess treatment efficacy  in vivo.

•   Pathologic data can help predict prognosis and potentially guide post-op treatment.

•   Immediate application of systemic therapy in a cancer where risk of systemic recurrence governs survival. 

The patient received 3 cycles of neoadjuvant therapy with combination cisplatin, pemetrexed, and pembrolizumab. During the 4^th cycle, carboplatin was substituted for cisplatin because of persistent nausea and vomiting and mild renal insufficiency, attributed to cisplatin (creatinine 1.55).  Four weeks after the last dose of neoadjuvant therapy there were no lingering toxicities and the creatinine had improved to 1.26. The patient underwent LUL resection which revealed a major pathologic response with more than 90% regression in the primary. Residual tumor measured 2.2 cm, but there were only scattered areas of viable carcinoma, mostly fibrosis and lymphocytic infiltration. Remaining invasive component measured < 0.5 cm, all nodes were negative, and the patient was downstaged to T1aN0 stage IA. 

References:

1.Pignon JP, Tribodet H, Scagliotti G et al Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group, J Clin Oncol 26; 3552-3559, 20087.

2.Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 7::719,2006-72

3.Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non–small-cell lung cancer. N Engl J Med 352::2589,2005-2597

4. Tsuboi, M, Herbst R, John T, et al Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 2023;389:137-147

5. Wu YL,  Dziadziuszko R, Ahn JS,Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer.  N Engl J Med 2024;390:1265-1276

6. Wakelee, H, Lieberman M; Kato T, et al  Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. N Engl J Med 2023;389:491-50

7. Spicer JD, Gao S, Liberman M, et al. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Ann Oncol 2023;34:Suppl 2:S1297-S1298. abstract

8. Liu J, Blake SJ, Yong MC, et al.. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 2016;6(12):1382-1399.