Preoperative immunotherapy combined with stereotactic body radiation to the primary tumor in patients with operable non-small cell lung cancer (NSCLC) significantly increased the proportion of patients who achieved a major or complete pathological response (pCR) compared with immunotherapy alone, a single-center, open-label, phase II trial found.
In a small cohort of 60 patients with stage I to IIIA NSCLC, a major pathological response was seen in 6.7% (95% CI, 0.8-22%) of patients treated with the immune checkpoint inhibitor durvalumab compared with 53.3% (95% CI, 34.3-71.7%) in the durvalumab plus radiotherapy group (P<0.0001), Nasser Altorki, MD, Weill Cornell Medicine-New York Presbyterian Hospital, New York, and colleagues reported in Lancet Oncology.
Of those who achieved a major pathological response in the dual therapy group, 50% achieved a pCR, investigators added.
Rates of grade 3 and 4 adverse events (AEs) occurred in similar numbers of patients in both treatment arms at 17% in the durvalumab monotherapy arm versus 20% in the durvalumab plus radiotherapy arm while two patients in each group had a serious AE, the authors noted.
“To the best of our knowledge, this is the first trial combining immune checkpoint inhibition (durvalumab) with stereotactic body radiotherapy (8 Gy x 3 fractions) as an immune modulator of the tumor immune microenvironment to enhance the efficacy of immune checkpoint blockade in the neoadjuvant setting in patients with lung cancer,” Altorki and colleagues wrote. “We found that the combination is safe, well tolerated, and associated with a significant enhancement of major pathological response, the primary endpoint of the trial.”
Patients were randomly assigned in equal numbers to durvalumab monotherapy or durvalumab plus stereotactic body radiotherapy.
“All patients were planned to receive two cycles of durvalumab three weeks apart at a dose of 1.122 g by intravenous infusion over 60 minutes,” the investigators explained. Patients in the durvalumab plus radiotherapy group received three consecutive daily fractions of 8 Gy initiated the same day as they received their first cycle of durvalumab.
The authors noted, since programmed cell death-ligand 1 (PD-L1) expression was not a stratification factor prior to randomization, more patients with PD-L1 negative tumors were assigned by chance to the durvalumab monotherapy group than to the combination group.
“All 30 patients in the monotherapy group received both cycles of durvalumab [while i]in the dual therapy group, all 30 patients received the first cycle of durvalumab combined with the planned stereotactic body radiotherapy (8 Gy x 3 fractions) with no delays in the radiotherapy schedule,” the authors wrote.
Some 87% of patients in each treatment group underwent surgical resection at a median interval of 5.3 weeks (interquartile range (IQR, 4.7-6.0 weeks) from the date of the first cycle of durvalumab. This is a considerably shorter interval than is commonly required when patients undergo preoperative chemotherapy or chemoradiotherapy and it was done so without incurring a higher risk of toxicity, the study authors pointed out.
Among those who did undergo surgical resection, complete resection (RO) was accompanied in 96% of the durvalumab plus radiotherapy group and 77% of those in the durvalumab monotherapy arm.
However, with a median follow-up of nine months (IQR, 8.3-27.7 months) after surgery, disease recurrence occurred in 15% of patients who had an RO section, in 13% after receiving preoperative durvalumab, and in 2% of patients after receiving preoperative durvalumab and radiotherapy.
As editorialists Boris Sepesi, MD, and Tina Cascone, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas pointed out, low-dose stereotactic body radiotherapy as used in the current study appears to induce greater frequencies of antigen-presenting cells and is thus able to produce higher rates of major pathological responses than immunotherapy alone.
This jibes with the authors’ suggestion that restoration of major histocompatibility complex (MHC)-1 expression—a common immune escape mechanism—may be one of the processes by which radiotherapy might enhance response to immune checkpoint blockade.
Sepesi and Cascone also recently reported initial results of a single-arm, phase II study of neoadjuvant chemotherapy plus nivolumab again in operable NSCLC at the 2021 annual meeting of the American Association for Cancer Research (abstract SY13-03). In their study, the major pathological response rate was 32% while the pCR rate was 18% which led to a 100% resection rate.
In the CheckMate-816 phase II trial also reported at the 2021 annual meeting of the American Association for Cancer Research (abstract CT003), resection rates at approximately 80% were very similar in patients who received nivolumab plus a platinum doublet versus chemotherapy alone but a pCR was achieved in 24% of patients in the combination arm versus only 2.2% in the chemotherapy alone arm.
“All future trials will be compared with CheckMate-816,” Sepesi and Cascone predicted given that it is the first, phase 3 neoadjuvant immunotherapy trial to show benefit of immune checkpoint inhibitors plus chemotherapy over chemotherapy alone.
Already, however, evidence makes it quite clear that an immune checkpoint inhibitor given in combination with chemotherapy or stereotactic body radiotherapy leads to a significantly higher proportion of pCR responses compared with chemotherapy alone.
Given that local and regional disease control should be achieved with complete RO resection in operable NSCLC, “the main goal of these [neoadjuvant] trials is to control eventual metastatic disease,” Sepesi and Cascone observed.
And while it is not yet known if either chemotherapy or an immune-priming dose of stereotactic body radiotherapy combined with immunotherapy will reduce distant recurrence rates, “the best treatment results will possibly come from more accurate patient selection and stratification for various treatment regimens,” Sepesi and Cascone noted, with still-to-come biomarkers identifying non-responders to novel treatments playing an important role.
-
Preoperative immunotherapy plus stereotactic body radiation significantly increased major pathological response rates compared with immunotherapy alone in patients with operable NSCLC.
-
Restoration of MHC-1 expression may be one way in which radiotherapy might enhance response to immune checkpoint blockade.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by AstraZeneca.
Atkorki reported having stock options from TMRW, Angiocrine Bioscience, and View Point Medical and is on the research advisory committee for AstraZeneca.
Sepesi reported receiving consulting fees from Bristol Myers Squibb and speaker fees from AstraZeneca while Cascone reported receiving consulting fees from MedImmune/AstraZeneca and Bristol Myers Squibb as well as advisory role fees from Bristol Myers Squibb, MedImmune/AstraZeneca, and EMD Serono. She has also received research funding to her institution from Boehringer Ingelheim, MedImmune/AstraZeneca, EMD Serono, and Bristol Myers Squibb.
Cat ID: 24
Topic ID: 78,24,730,24,192,65,925
