Perioperative durvalumab-based therapy reduces risk for adverse lung cancer outcomes
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Key takeaways:
- The regimen improved both EFS and pathologic complete response rates vs. neoadjuvant chemotherapy alone.
- The results may lead to multiple new choices for patients with resectable non-small cell lung cancer.
Patients with resectable non-small cell lung cancer who received perioperative durvalumab with neoadjuvant chemotherapy had significantly longer EFS and higher pathologic complete response rates than those who received chemotherapy alone.
The combination also had a manageable safety profile consistent with previous studies, according to results of the randomized, double-blind phase 3 AEGEAN trial, presented at American Association for Cancer Research Annual Meeting.
“It’s incredibly encouraging that patients with resectable non-small cell lung cancer are likely to have multiple choices now moving forward,” John V. Heymach, MD, PhD, professor and chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, said during a press conference. “Recurrences are still, unfortunately, common.”
Background and methods
Immunotherapy with PD-1/PD-L1 inhibitors has shown benefit in phase 3 trials in either the neoadjuvant or adjuvant resectable NSCLC setting, Heymach said.
“Perioperative regimens that combine these two approaches could potentially enhance the benefits by priming antitumor immunity while the tumor and draining lymph nodes are still in place. And by having the sustained PD-1 pathway inhibition after surgical resection, you could help eradicate micrometastases,” he said.
The AEGEAN trial assessed the anti-PD-L1 antibody durvalumab (Imfinzi, AstraZeneca) as neoadjuvant therapy in combination with platinum-based chemotherapy and as adjuvant therapy among patients with treatment-naive, resectable NSCLC, regardless of PD-L1 expression.
Researchers randomly assigned 802 patients to either durvalumab dosed at 1,500 mg via IV every 3 weeks for four cycles plus chemotherapy, followed by surgery and 1,500 durvalumab every 4 weeks for 12 cycles, or the same regimen with placebo instead of durvalumab. They stratified randomization according to disease stage (II vs. III) and PD-L1 expression.
The efficacy analyses included 740 patients (median age, 65 years) in the modified intention-to-treat population without documented EGFR or ALK alterations. One-third of patients in each group had PD-L1 expression of less than 1% of tumor cells, about 70% had stage IIIA or IIIB disease, and nearly half had N2 nodal involvement.
Pathologic complete response per central lab review and EFS by blinded independent central review served as the primary endpoints. Major pathologic response, DFS and OS served as secondary endpoints.
Median follow-up at first planned EFS analysis was 11.7 months (range, 0-46.1).
Results
Similar proportions of patients in the durvalumab and placebo groups completed at least four cycles of platinum-doublet chemotherapy (84.7% vs. 87.2%) and surgery (77.6% vs. 76.7%).
Results of the interim EFS analysis showed the durvalumab group had a 32% lower risk for disease recurrence, progression or death than the placebo group (stratified HR = 0.68; 95% CI, 0.53-0.88).
Researchers observed the EFS benefit across subgroups, with a larger magnitude among current smokers (HR = 0.48; 95% CI, 0.28-0.8) and smaller magnitude among patients with stage IIIB disease (HR = 0.83; 95% CI, 0.52-1.32) and PD-L1 expression of less than 1% (HR = 0.76; 95% CI, 0.49-1.17). Heymach noted that patients derived an EFS benefit with durvalumab regardless of planned neoadjuvant platinum agent (cisplatin, HR = 0.59; 95% CI, 0.35-1; carboplatin, HR = 0.73; 95% CI, 0.54-0.98).
Results of the final analysis of pathologic response showed the durvalumab group had significantly higher rates of pathologic complete response (17.2% vs. 4.3%; difference, 13 percentage points; 95% CI, 8.7-17.6) and major pathologic complete response (33.3% vs. 12.3%; difference, 21 percentage points; 95% CI, 15.1-26.9).
The durvalumab and placebo groups had similar rates of grade 3 or grade 4 adverse events (42.3% vs. 43.4%), with a higher rate of grade 3 or grade 4 immune-related adverse events in the durvalumab group (4% vs. 2.5%).
Next steps
Perioperative durvalumab and neoadjuvant chemotherapy represents a potential new treatment for patients with resectable NSCLC, according to Heymach.
“Moving forward now, one imagines that perioperative therapy may serve as a platform to consider intensification strategies where needed for patients who didn’t have a complete response,” he said during the press conference. “We look forward to future studies thinking about how to reduce the recurrence rates that are still higher than we would like.”
Perspective
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Jorge J. Nieva, MD
The addition of PD-1 checkpoint inhibition to chemotherapy improves survival for patients with early-stage lung cancer who undergo resection. This principle has now been confirmed by four different trials involving four different checkpoint inhibitors.
First came the IMpower010 trial, which showed 1 year of adjuvant atezolizumab (Tecentriq, Genentech) in patients with resected stage IB to stage IIIA disease with a PD-L1 score of 1% or more resulted in fewer relapses and deaths due to lung cancer.
Next came CheckMate -816, a neoadjuvant trial showing the addition of nivolumab (Opdivo, Bristol Myers Squibb) to preoperative chemotherapy reduced the risk for both relapse and death.
The benefits of adjuvant therapy observed in IMpower010 were confirmed in a similar trial of pembrolizumab (Keytruda, Merck), KEYNOTE-091, which showed a reduction in relapse and death among patients treated with the agent for 1 year.
Now we have AEGEAN, which showed both neoadjuvant and adjuvant therapy results in benefits similar to those seen in CheckMate -816.
There is now clear evidence that the addition of a checkpoint inhibitor to (neo)adjuvant chemotherapy provides significant benefit. Health care payors who are not covering or providing these drugs for patients with early-stage lung cancer are clearly out of step with contemporary data.
But how much checkpoint inhibitor is needed? Only three cycles demonstrated the survival benefit in CheckMate -816, but 1 year of postoperative therapy was used in IMpower010 and in AEGEAN. Is the adjuvant portion of treatment necessary? How much benefit does adjuvant treatment add to neoadjuvant treatment?
There is a strong biological case in favor of neoadjuvant therapy. Tumor-draining lymph nodes appear to play an important role in tumor antigen processing, and the benefits to checkpoint inhibitor therapy may be greater when these lymph nodes are still in place, as is the case with neoadjuvant treatment. This may explain the somewhat larger benefits seen in AEGEAN and CheckMate -816 as compared with IMpower010 and KEYNOTE 091, which administered therapy following a surgical lymph node dissection.
Pharmaceutical companies will bring us future trials of neoadjuvant atezolizumab (IMpower030), as well as trials of neoadjuvant and adjuvant pembrolizumab (KEYNOTE-671), and publication of these results is anticipated soon. But these industry trials will not answer the question of whether adjuvant therapy adds benefit after neoadjuvant treatment.
Given the high cost of checkpoint inhibitor therapy, the question of the duration of checkpoint inhibition is important for the health care system. This will have to be a question for another trial. Ideally, this would be the type of trial conducted by NCI and the cooperative groups. In the meantime, we are unencumbered by data as to which approach is best; and that means that individual physicians will use their personal judgement to decide on the timing and duration of checkpoint inhibitors for their patients with early-stage lung cancer.
References:
Clinicaltrials.gov. A study of neoadjuvant atezolizumab plus chemotherapy versus placebo plus chemotherapy in patients with resectable stage II, IIIA, or select IIIB non-small cell lung cancer (IMpower030).
Clinicaltrials.gov. Efficacy and safety of pembrolizumab (MK-3475) with platinum doublet chemotherapy as neoadjuvant/adjuvant therapy for participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (MK-3475-671/KEYNOTE-671).
Girard N, et al. Abstract CT012. Presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
Paz-Ares L, et al. Abstract VP3-2022. Presented at: ESMO Virtual Plenary; March 17, 2022.
Wakelee HA, et al. Abstract 8500. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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Heymach JV, et al. Abstract CT005. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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