Dr Chaft Presents Progress for Immune Checkpoint Inhibitors in NSCLC

Jamie E. Chaft, MD, Memorial Sloan Kettering Cancer Center, New York, presented an introduction of immune checkpoint inhibitors (CPIs) in the curative setting of neoadjuvant and adjuvant therapy in resectable non-small cell lung cancer (NSCLC) at the virtual Personalized Therapies in Thoracic Oncology.

Dr Chaft highlighted the clinical need to move CPIs beyond perioperative chemotherapy, which is supported by decades of data showing that cisplatin-based chemo can improve survival in patients with resected NSCLC. However, the survival advantage across advanced stages is only 5% in 5 years, and many patients are refractory to cis-platin chemo. 

“We can do better. Perhaps checkpoint inhibitors are part of that equation. Those of us who focus our efforts in early-stage lung cancer are chasing progress that is achieved in advanced disease. There are many approvals leading to new therapies, either targeted, chemo or immunotherapies, but progress still needs to be made in adjuvant or neoadjuvant studies,” said Dr Chaft.

There has been minimal progress in advances for the treatment of resectable NSCLC. In 2005, adjuvant cisplatin doublet chemotherapy was standardized. However, five years later, neoadjuvant meta-analysis showed that neoadjuvant and adjuvant therapies are equivalent. In 2020, the FDA approved osimertinib as a targeted therapy for disease-free survival advantage.

To date, there is no available standardized immunotherapy (IO) options for resectable NSCLC.

“There are signals of efficacy with IO for this patient population. In a study I took part in from 2018, we challenged a very small cohort with 2 doses of neoadjuvant PD-1 therapy with nivolumab. We found a surprising efficacy signal in terms of pathologic progression. 4 weeks of therapy showed a 41% major pathologic response rate (MPR),” continued Dr Chaft.  

Further in the study, complete pathologic responses (pCR) were observable in this neoadjuvant setting. 

The Lung Cancer Mutation Consortium model, a larger clinical trial with an accurate representation of true pathologic response rates, enrolled 180 patients with resectable NSCLC and prescribed two doses of atezolizumab once every three weeks for six weeks of therapy. The MPR rate was 21%, and the pCR rate was 7%. 

Multiple predictive biomarker assays show the potential to identify patients who can have their entire tumor completely removed preoperatively with PD1 or PD-L1 monotherapy. 

“We need to ask, can adding chemo potentially abrogate a durable antitumor immune response? Who benefits from chemo or monotherapy? Certainly, we need better predictive biomarkers, until then, this approach cannot be expanded,” said Dr Chaft.

Dr Chaft elaborated on the significant benefit of neoadjuvant platinum-taxane-IO combinations. One study observed atezolizumab, carboplatin, and nab-paclitaxel chemotherapy followed by surgery in a high-risk population of patients with stage 3 NSCLC to find a 57% MPR rate, and notably, a 33% PCR rate. 

“This is a rate that we anticipate from the historic literature to happen less than 5% of the time with chemo alone. This is very compelling data, and it was replicated in the NADIM study,” explained Dr Chaft.

In this study, a combination of carboplatin, paclitaxel, and three cycles of nivolumab (NV) followed by adjuvant NV treatment for one year was provided to patients with resectable stage IIIA NSCLC. 91% (41 of 45) were resected, with a 74% MPR rate and a 57% pCR rate. Dr Chaft recommended further investigation and large data sets of event-free (EFS) survival through IO.

“While we are waiting data of EFS, there is sufficient evidence to suggest that adding anti-P1 to neoadjuvant chemo induces greater tumor kill, a greater complete resection rate, and may enable more lung spare resection surgeries or fewer pneumonectomies,” said Dr Chaft.

For adjuvant IO, multiple studies were launched internationally. Over 4,650 patients have been enrolled with prescribed therapies after chemo in a randomized setting. These studies include CCTG Durvalumab, EA5142 NV, IMpower010 Atezolizumab, and PEARLS Pembrolizumab.

The first study to publish results for adjuvant IO was IMpower010 with data presented at ASCO 2021 for patients with completely resected stage IB-IIIA NSCLC who received or did not complete cisplatin chemo.

“While this trial met a significant threshold and showed statistical significance, the data was slightly less compelling, but demonstrated better improvements than chemo,” continued Dr Chaft.

Notably, previous studies have shown that patients with oncogene-driven tumors are unlikely to benefit from CPIs, including in the perioperative setting.

Patients with epidermal growth factor receptor (EGFR) mutations or positive anaplastic lymphoma kinase (ALK)+ disease did not benefit from atezolizumab, nor did non-smokers. However, there were significant benefits for those with high PD-L1 expressions, but not PD-L1 negative tumors.

“As we introduce CPIs into the curative setting, there is progress being made. Adjuvant atezolizumab will be a new standard of care for patients with resected PD-L1 high tumors. The benefit of adjuvant atezolizumab after resection of a tumor with 1-49% PD-L1 expression is unclear. More work is needed to improve outcomes for patients with PD-L1 negative tumors,” said Dr Chaft.

Neoadjuvant chemo-IO appears promising, particularly for large or high-risk tumors. Other neoadjuvant studies will prove difficult to interpret as each has an adjuvant phase with complex path endpoints and EFS.

“Moving forward, IO clearly has a role for some patients with early-stage lung cancer. Adenocarcinoma and squamous cell carcinoma are different diseases and should be studied separately. We need to determine which oncogenes benefit in the adjuvant setting. Ultimately, we need to compare preop IO to postop IO,” concluded Dr Chaft. – Alexa Stoia