Stage IIIA disease accounts for approximately 15% to 20% of all lung cancers. Th is very heterogeneous population of patients is mainly characterized by their potential curability, but prognosis varies greatly depending on the degree of lymph node involvement at the time of diagnosis.
Patients with stage IIIA disease with clinically evident N2 nodal spread have a 5-year OS rate of just 15% to 20%, although this can fall to 5% to 10%1 in those with bulky mediastinal N2 involvement. The standard of care for most patients, particularly those with visible nodal involvement on either CT or PET, remains concurrent chemotherapy and radiation.
The surgical management of stage IIIA NSCLC remains highly controversial. At least 80% of patients treated with local modalities alone will have micrometastases and relapse. The aim of therapy in stage III NSCLC is to increase both locoregional and systemic control of the disease.
Neoadjuvant therapy has theoretical advantages: in vivo assessment of response to chemotherapy, which helps to identify those patients who will potentially benefit from chemotherapy; early treatment of micrometastatic disease; potential downstaging with improved resectability; and the possibility of identification of surrogate clinical and biological markers that may correlate with response to therapy and potential long-term outcome.
During the last 25 years, we have not observed significant advances in this group of patients, and neoadjuvant chemotherapy alone remains the standard of care for those in whom surgery is still a possibility. Combinations with targeted therapies, induction with radiochemotherapy, and other treatment modalities have been tried without any meaningful effect on OS rates. Th e most significant prognostic factors remain complete resection, downstaging, and pathologic response following induction. In contrast to other tumor types, pathologic response rate—even pathologic complete response (pCR)—has not been successfully established as a surrogate for OS, largely because the OS reported by the different clinical trials in the neoadjuvant setting is less than 8%.2
The NADIM trial was the first to test combination chemotherapy and immunotherapy as induction therapy in a very homogenous stage IIIA patient population with histologic confirmation of N2 involvement. A total of 46 patients were included. None of the patients withdrew from the study preoperatively due to progression or toxicity, two patients decided not to undergo resection, and three did not fulfill surgical criteria for resectability. A total of 42 patients underwent surgery, and all tumors were deemed resectable with R0 resection in all cases. Major pathologic response was achieved in 34 of 41 patients (82.9%), 26 of whom (63.4%) had pCR. Down-staging was achieved in 37 of 41 patients (90.2%) and OS at 20 months was 90%.3
Currently, a number of trials are studying neoadjuvant therapy, although none solely in stage IIIA disease.
The LCMC3 trial3,4 is a phase II singlearm study of neoadjuvant atezolizumab monotherapy in patients with resectable early-stage NSCLC. According to reports on the first 101 of 180 planned patients, six out of 82 patients had partial response, 72 had stable disease, and four had progressive disease. The major pathologic response (MPR) rate was 18%, and 5% had pCR.
The NEOSTAR trial is a randomized phase II study of induction checkpoint blockade for patients with untreated stage I-IIIA (single N2) NSCLC. Patients received three doses of nivolumab (3 mg/kg) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 2 weeks followed by surgery. Five of the 31 patients initially scheduled for surgery did not proceed to resection (one with grade 3 hypoxemia, two with high surgical risk, two with disease that was no longer resectable). Among the 26 patients who underwent resection, the MPR rate was 28% with nivolumab and 31% with the combination. Updated data were presented at the 2019 American Society of Clinical Oncology Annual Meeting: 39 of 44 patients underwent surgery (89% resectability). MPR rate was 24% overall; 17% with nivolumab and 33% with the combination therapy.6
The results of several studies with combination chemotherapy and immunotherapy are awaited and are outlined here.
• Neoadjuvant chemotherapy plus atezolizumab (NCT 02716038): four cycles of atezolizumab plus carboplatin nabpaclitaxel reported an MPR of 64% in 11 patients who underwent resection.
• KEYNOTE-671 trial (NCT 03425643): Effi cacy and Safety of Pembrolizumab (MK-3475) With Platinum Doublet Chemotherapy as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage IIB or IIIA Non-small Cell Lung Cancer.
• CheckMate-816 (NCT 02998528): a phase III open-label study that initially had three arms, but the nivolumab plus ipilimumab arm has been closed early. This study will compare event-free survival (EFS) and pCR rates among participants treated with neoadjuvant nivolumab plus platinum doublet chemotherapy versus platinum doublet chemotherapy alone in stage IB-IIIA NSCLC.
• IMpower-030 (NCT03456063): a trial with the surrogate objective MPR as its primary endpoint. Randomization is between four cycles of platinum doublet chemotherapy with atezolizumab or placebo, followed by surgery and postoperative standard of care in patients with stage II-IIIAIIIB (T3N2) disease.
• 77T trial (NCT04025879)—A Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant Chemotherapy Plus Placebo, Followed by Surgical Removal and Adjuvant Treatment With Nivolumab or Placebo in Early Stage Non-small Cell Lung Cancer: includes patients with suspected or histologically confirmed, resectable stage IIA-IIIB NSCLC. The primary endpoint is EFS as assessed by blinded independent central review.
• NADIM II (NCT03838159): an openlabel, randomized, two-arm, phase II, multi-center clinical trial. Patients randomly assigned to the experimental arm will receive nivolumab plus paclitaxel plus carboplatin for three cycles every 21 days as neoadjuvant treatment followed by surgery and 6 months of adjuvant treatment with nivolumab. Th e primary objective is pCR, defi ned as the absence of residual tumor in lung and lymph nodes. This trial compares neoadjuvant chemoimmunotherapy to neoadjuvant chemotherapy alone. Many of the studies discussed include very different populations, which makes it difficult to draw firm conclusions for diverse stages or presentations. Homogeneous populations should be studied in very limited scenarios designed to answer a specific question. My personal impression is that studies with chemoimmunotherapy provide a higher rate of pathologic responses and downstaging than previous studies conducted solely with chemotherapy. On the other hand, it remains to be confirmed whether pCR is a sufficient surrogate for OS. In addition, no molecular markers predicting increased survival and/or response in the immunotherapy setting have been reported to date. For that, longer follow up evaluating PFS and OS are expected, particularly from the NADIM study. On the other hand, if the differences in outcome afforded by chemoimmunotherapy treatment are so striking compared to standard chemotherapy alone, the question remains as to whether we should wait for conventional studies of several years’ duration with hundreds of patients to produce a change in standard practice that seems highly evident and plausible given the results in advanced disease and in phase II testing.
1. Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassifi cation and implications.
J Clin Oncol. 2000;18(16):2981-2989.
2. Hellmann MD, Chaft JE, William WN, Jr., et al. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 2014;15:e42-50.
3. Provencio M, Nadal E, Insa A, et al. NADIM Study: Updated Clinical Research and Outcomes. Presented at IASLC World Conference on Lung Cancer; Barcelona, Spain; September 10, 2019.
4. Rusch VW, Chaft JE, Johnson BE, et al. Neoadjuvant Atezolizumab in resectable nonsmall cell lung cancer (NSCLC): updated results from a multicenter study (LCMC3). J Th orac Oncol. 2018;36 Suppl:Abstract MA04.09.
5. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current status and future perspectives on neoadjuvant therapy in lung cancer. J Th orac Oncol. 2018;13(12):1818-1831.
6. Cascone T, Williams WN, Weissferdt A, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol. 2019;37(no. 15_suppl):8504.