The integration of immunotherapy with traditional chemoradiotherapy has significantly increased pathologic complete response rates in patients with non–small cell lung cancer (NSCLC), according to data presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.1
Findings from the open-label, nonrandomized INCREASE trial showed dual immunotherapy with ipilimumab and nivolumab added to chemoradiotherapy led to a 60% complete pathologic response rate in locally advanced resectable NSCLC—a nearly twofold increase compared with traditional chemoradiotherapy alone. Despite the increased intensity of the regimen, authors of the study reported the treatment was well tolerated by most patients, and treatment-related adverse events were manageable.
Chris Dickhoff, MD, PhD
“Adding immunotherapy to the standard chemoradiotherapy has shown a significant increase in complete pathologic response in patients who we would normally consider for induction chemoradiotherapy,” said lead study author Chris Dickhoff, MD, PhD, Medical Specialist, Cardiothoracic Surgery, Amsterdam University Medical Centers, the Netherlands. “This changes the landscape of treatment strategies for locally advanced NSCLC.”
Background
For resectable, locally advanced NSCLC, induction therapy comprising chemotherapy, chemotherapy plus radiotherapy, or more recently chemotherapy plus immunotherapy is the recommended treatment approach. For large-volume tumors and tumors invading surrounding structures such as the thoracic wall, chemoradiotherapy is the preferred induction approach, resulting in pathologic complete response rates of approximately 30% to 35%,2 said Dr. Dickhoff, who noted that high pathologic complete response rates have been shown to correlate with better overall survival after all induction therapies. Despite advances in chemotherapy and radiation treatment, however, survival rates for NSCLC have remained stagnant.
INCREASE Trial Design
For the INCREASE trial, Dr. Dickhoff and colleagues hypothesized that the addition of immunotherapy to conventional chemoradiotherapy would enhance pathologic complete response rates. Patients with clinical T3–T4 NSCLC who normally would be considered for induction chemoradiotherapy were eligible. A single dose of dual immunotherapy with the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab was administered concurrently with chemoradiotherapy, and a second dose of nivolumab was administered at the start of the second cycle of chemotherapy. A radiotherapy dose of 50 Gy was planned for most patients, except those considered to be borderline resectable (and they received 60 Gy).
Following completion of induction treatment, investigators evaluated patients for restaging using PET, CT, and MRI of the brain. Provided there was an absence of disease progression, said Dr. Dickhoff, patients were scheduled for surgery, which was typically an anatomic resection. The study’s primary endpoints were pathologic complete response, major pathologic response, and safety.
Outcomes Improved With Combination Therapy
As Dr. Dickhoff reported, 29 of 30 patients completed the induction phase, and 26 patients underwent successful operation, of whom 25 were analyzed. The median age of the patients in the trial was 64 years, and the histology was predominantly adenocarcinoma. Most patients enrolled on the study had stage IIIA NSCLC (76%).
The research findings revealed that dual immunotherapy plus chemoradiotherapy resulted in a marked improvement in patients’ outcomes, with a pathologic complete response rate of 60%. “This figure is impressive,” said Dr. Dickhoff, especially when compared with traditional induction trials using solely chemoradiotherapy, which typically attain pathologic complete response rates of approximately 30% to 35%.
Although 100% of patients who started induction therapy experienced treatment-related adverse events, most of these side effects were manageable, according to Dr. Dickhoff. A total of 20% experienced grade 3 or 4 morbidity, according to Clavien-Dindo classification, and no patients failed to undergo surgery because of a treatment-related adverse event. Unfortunately, one patient developed pneumonitis on day 96 after surgery and died of what was likely an immune-related adverse event, Dr. Dickhoff concluded.
DISCLOSURE: Dr. Dickhoff reported financial relationships with Bristol Myers Squibb, AstraZeneca, and Ineligible.
REFERENCES
1. Dickhoff C, Heineman DJ, Schneiders FL, et al: Surgery after neoadjuvant immuno-chemoradiotherapy in potentially resectable NSCLC: Results from the INCREASE trial. 2023 World Conference on Lung Cancer. Abstract OA06.04. Presented September 10, 2023.
2. Eberhardt WE, De Ruysscher D, Weder W, et al: 2nd ESMO Consensus Conference in Lung Cancer: Locally advanced stage III non-small-cell lung cancer. Ann Oncol 26:1573-1588, 2015.
