Is It Time to Add Checkpoint Inhibitors to the Treatment of Locally Advanced Lung Cancer?

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After more than 20 years of failed strategies to improve survival rates for locally advanced lung cancers, checkpoint inhibitors have revolutionized therapy, but prognoses still lag behind other tumor types. During the ASCO20 Virtual Education Program, Mark G. Kris, MD, FASCO, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York, discussed the potential for adding immunotherapy to local therapies, weighed the benefits of neoadjuvant versus adjuvant chemotherapy, and urged his colleagues to reimagine care for localized lung cancers.1

Mark G. Kris, MD, FASCO

Mark G. Kris, MD, FASCO

“To achieve optimal results, we must pay closer attention to sequence, timing, and sequential or concomitant use,” said Dr. Kris. “With more modalities, more agents, and less lifestyle disruption, we can do a better job.”

Rewriting Years of Disappointment

As Dr. Kris reported, of the estimated 229,000 cases of lung cancer diagnosed annually in the United States, approximately 78,000 are classified as locally advanced, which would represent the fourth most common cancer. “There are a huge number of patients with locally advanced lung cancer, which means there’s a huge opportunity for us to impact lives and do so in a curative setting,” said Dr. Kris.

This opportunity comes after years of failed treatment strategies. Adding consolidation chemotherapy, administering irradiation twice daily, using targeted therapies in patients with tumors without the target, and increasing the radiation dose all have failed to make an impact, according to Dr. Kris, and the latter two strategies actually decreased survival.

Ultimately, progress came with the phase III PACIFIC trial, which randomly assigned patients with stage III non–small cell lung cancer (NSCLC) to receive the anti–PD-L1 checkpoint inhibitor durvalumab or placebo after two or more cycles of platinum-based chemotherapy.2 Progression-free survival at 18 months with durvalumab was 44% versus 27% with placebo, and updated data have shown a 13% improvement in overall survival.3

“After 2 decades of disappointment, this is a fantastic development,” commented Dr. Kris.

The Problem of Systemic Relapse

As Dr. Kris explained, when patients with locally advanced lung cancer fail to respond to treatment, it’s almost always systemic. Therefore, eradicating and preventing metastases must be the priority.

“We actually do a very good job with surgery or radiation, but 80% of patients with local and regional disease fail systemically,” said Dr. Kris. “We do have some local failures, but it will be very difficult to show a benefit there.”

According to Dr. Kris, the path forward to cure is combining systemic therapies with surgery and radiation therapy. Although there are plenty of treatment modalities in the armamentarium, more modalities mean more toxicity. When adding another treatment modality, efficacy must be improved, said Dr. Kris. Equivalence in use of three modalities vs two modalities is a failure because of the increased toxicity from an additional modality of treatment. That said, all patients with lung cancer are candidates for additional therapies.

Dr. Kris noted that  in HER2-amplified breast cancers, data have demonstrated 94% median 2-year invasive disease–free survival with adjuvant neratinib versus placebo after chemotherapy and 1 year of trastuzumab.4

“If we have a safe strategy that can improve disease-free survival at 2 or 5 years, then it’s worth doing.”
— Mark G. Kris, MD, FASCO

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“This is the way we have to look at disease in lung cancer,” said Dr. Kris. “If we have a safe strategy that can improve disease-free survival at 2 or 5 years, then it’s worth doing.”

Neoadjuvant vs Adjuvant Chemotherapy

One treatment strategy that has proven effective is adding chemotherapy to surgery. According to Dr. Kris, both neoadjuvant and adjuvant cisplatin-based therapies have improved 5-year survival by approximately 5%, but neoadjuvant therapy is the preferred approach because it attacks micrometastases at the earliest possible time. Using neoadjuvant therapy also gives providers the chance to assess the sensitivity of agents that will be used in the adjuvant setting as well as those used in induction.

In addition, data have shown that both complete and major pathologic responses to neoadjuvant therapy are surrogate markers of long-term outcomes, and the drugs are better tolerated preoperatively, too. Compliance is improved, even with subsequent therapies, Dr. Kris added. Finally, there’s the practical benefit of having time to identify suspected metastases and comorbidities before local therapy.

Conversely, although neoadjuvant therapy is based on clinical stage, adjuvant therapy affords the advantage of precise staging. “The resection specimen is also an excellent source of tissue,” said Dr. Kris. “It’s the tissue that is persisting and posing a threat to the health and life of the patient.”

Finally, adjuvant therapy is the preferred approach for kinase inhibitors, particularly in oncogene-driven cancers. Examples include imatinib in gastrointestinal stromal tumors and osimertinib in EGFR-mutated lung cancers, which have demonstrated longer progression-free and overall survival.

Neoadjuvant Immunotherapy

Administering neoadjuvant immunotherapy may be another option. Preclinical data have shown that neoadjuvant combined immune checkpoint blockade prolongs survival and reduces lung metastases compared with adjuvant therapy.5 In addition, results from the phase II NEOSTAR trial demonstrated an overall major pathologic response rate of 33% in patients with early-stage, resectable NSCLC treated with neoadjuvant nivolumab plus ipilimumab.6

“The locoregional tumor microenvironment may provide a better chance for checkpoint inhibitors to work,” Dr. Kris explained. “The consensus is that there is a benefit with the neoadjuvant approach, and when you combine immunotherapy with chemotherapy, the benefit is even greater.”

“The locoregional tumor microenvironment may provide a better chance for checkpoint inhibitors to work.”
— Mark G. Kris, MD, FASCO

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There are six ongoing phase II trials testing pathologic and molecular complete responses after neoadjuvant immune checkpoint inhibition alone or with chemotherapy in patients with resectable and operable stage I to III lung cancers. There are also several phase III trials of immune checkpoint inhibitors in both adjuvant and neoadjuvant settings, said Dr. Kris, although definitive data from them may be many years away.

Regardless of the outcomes of these trials, however, Dr. Kris emphasized that increasing the cure rate will require multidisciplinary effort. “All members of the multimodality team need to promote and support the overall regimen and not just individual components,” Dr. Kris stated. “We have to work together…. By tapping into all the tools we have and all the experts we have, we will make the greatest impact for our patients.” 

DISCLOSURE: Dr. Kris has served as a consultant to AstraZeneca, Daiichi Sankyo, and Pfizer.


1. Kris MG: Making checkpoint inhibitors part of treatment for patients with locally advance lung cancers: The time is now. ASCO20 Virtual Education Program.

2. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.

3. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342-2350, 2018.

4. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367-377, 2016.

5. Cascone T, Hamdi H, Zhang F, et al: Superior efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-small cell lung cancer. 2018 American Association for Cancer Research Annual Meeting. Abstract 1719.

6. Cascone T, William WN, Weissferdt A, et al: Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer: Clinical and correlative results from the NEOSTAR study. 2019 ASCO Annual Meeting. Abstract 8504. Presented June 1, 2019.