Immunotherapy Takes First Major Step Into Earlier NSCLC

Liam Davenport

May 19, 2021

Updated June 8, 2021 // Editor's note: This story has been updated with comments from invited discussant Dr Zofia Piotrowska.

Immunotherapy has already had a huge impact on treatment of patients with later stages of non-small cell lung cancer (NSCLC): new clinical data are now showing benefits in patients with earlier stage disease.

Patients with stage IB-IIIA NSCLC showed a markedly improved disease-free survival (DFS) when atezolizumab (Tecentriq) was added onto adjuvant chemotherapy following resection, according to results from an interim analysis of the IMpower010 study.

Notably, the benefit with atezolizumab vs best supportive care was greatest in patients with expression of programmed death ligand 1 (PD-L1) on their tumor, in whom the DFS improvement was a significant 34%.

This is the "first global phase III trial using an immune checkpoint inhibitor to show a disease-free survival outcome in early stage NSCLC," said lead researcher Heather Wakelee, MD, professor of medicine and chief of the Division of Oncology at Stanford University Medical Center, Stanford, California.

She was speaking at a press briefing ahead of next month's annual meeting of the American Society of Clinical Oncology, where the results will be presented on June 6.

Wakelee added that the "planned analysis for disease-free survival and overall survival in the intention-to-treat populations will continue with longer-term follow-up."

Asked whether the drug could be recommended for these patients based on the current results, Wakelee said that "obviously we need approval" for this use from the US Food and Drug Administration, but she added that "the FDA has approved other agents, particularly most recently osimertinib [Tagrisso], based on a disease-free survival endpoint."

These new results show that the benefit with atezolizumab plus chemotherapy  is "more profound" than with chemotherapy plus best supportive care, "and therefore, to me, it would be something I would want to offer my patients in that setting."

Wakelee also emphasized the importance of screening for lung cancer, so that the disease is detected at earlier stages "when it is potentially curable."

She also stressed the importance of biomarker testing for patients with resected disease "to look for EGFR mutations, which can be treated with EGFR TKIs and also, at some point, to check for PD-L1…because, in this trial, the vast majority of benefit" appeared to be in those with PD-L1 expression on their tumors.

Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said that "immune checkpoint inhibitors have certainly changed the treatment landscape for many types of cancers" and the current study "is the first time we've seen an immunotherapy that's effective in treating early stage NSCLC."

"This is an important advance in understanding the role of immunotherapy in earlier stage lung cancer" and "potentially a step forward for many patients."

Study Details 

The standard of care for many stage IB-IIIA NSCLC patients "has not changed for many years," despite "significant progress" having been made in the treatment of more advanced disease, Wakelee commented.

Consequently, the majority of patients with resected NSCLC continue to receive adjuvant platinum-based chemotherapy, which has been shown to reduce the risk of disease recurrence by 16% in those with completely resected disease.

The new study set out to examine the benefit of adding atezolizumab to adjuvant chemotherapy in the global phase III IMpower010 study.

Patients had to have stage IB-IIIA NSCLC, with stage IB tumors ≥4 cm in size, and tumor tissue available for PD-L1 analysis. Following complete resection, 1280 patients were given up to four cycles of adjuvant platinum-based chemotherapy.

Of those, 1005 patients were then randomly assigned 1:1 to receive either 16 cycles of atezolizumab 1200 mg IV every 3 weeks or best supportive care.

The interim results show that, after a median follow-up of 32.8 months, the addition of atezolizumab significantly reduced the risk of recurrence or death vs best supportive care in patients whose tumors had PD-L1 expression ≥1%, at a hazard ratio of 0.66 (P = .004).

At 24 months, the DFS rate was 74.6% among patients given atezolizumab versus 61% in those receiving best supportive care, reducing to 60% and 48.2%, respectively, at 36 months.

When looking across all randomized patients, the addition of atezolizumab was associated with a smaller reduction in the risk of recurrence of death vs best supportive care, at a hazard ratio of 0.79 after a median follow-up of 32.2 months (P = .02).

On the intention to treat analysis, the reduction in the risk of recurrence or death with atezolizumab was of borderline significance, at a hazard ratio of 0.81 after a median follow-up of 32.2 months (P = .04).

Wakelee pointed out that patients with stage IB disease, who represented around 12% of those in the trial, "tend to do better and we require longer time to see some of the disease recurrence outcomes," and so these results are "preliminary."

She also emphasized that the overall survival data are not yet mature and survival was not formally tested in the current analysis.

In terms of safety, the adverse event profile with atezolizumab was consistent with previous reports, the investigators noted in the abstract. However, Wakelee said at the briefing that "we had to stop treatment with atezolizumab in 18% of patients because of toxicity."

All-grade adverse events were reported in 70.7% of the best supportive care group vs 92.7% among those given atezolizumab, while grade 3-4 adverse events were reported in 11.5% and 21.8% of patients, respectively.

Immune-related adverse events were reported for 51.7% of patients taking atezolizumab, of which 7.9% were grade 3-4, vs 9.5% and 0.6%, respectively, in the placebo group. The most common grade 3-4 events in the active treatment group were hepatitis (4%), rash (1.4%), and pneumonitis (0.8%).

Invited to discuss the results, Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center, Boston, said the study was, overall, "well-designed and robust."

She added that, "as we might have predicted, the benefit of adjuvant atezolizumab was greatest among patients with the highest PD-L1 expression…on the other hand, patients with negative PD-L1 did not benefit."

Asking whether a DFS endpoint is "sufficient" to change clinical practice, Piotrowska noted that, while overall survival has been considered the "gold standard" for adjuvant studies, "overall survival data takes years to mature and, in the meantime, we have to make decisions with the data at hand.

"I would argue that, as a clinician, and I think from a patient and caregiver perspective, disease-free survival is an important endpoint."

She continued that "ultimately, the question of clinically meaningful benefit is up to the regulatory bodies," and recent approvals by the US Food and Drug Administration suggest DFS "is now accepted as a clinically meaningful endpoint that can be used to guide practice."

"If we as a community don't feel that DFS is a clinically meaningful endpoint, it's incumbent upon us to reflect this in the design of future adjuvant studies," Piotrowska added.

Returning to IMpower010, she said, "It remains to be seen whether these DFS data will translate into overall survival benefit with longer follow-up, but I'm optimistic based on our experience in the metastatic and unresectable stage III setting that adjuvant immunotherapy does have the potential to increase cures."

As they currently stand, the results are "sufficient for me to recommend, or at least consider, adjuvant atezolizumab for PD-L1-positive patients once FDA approved," Piotrowska said.

The study was funded by Hoffmann-LaRoche.

Wakelee reports relationships with AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Helsinn Therapeutics, Janssen Oncology, Mirati Therapeutics, Xcovery, ACEA Biosciences (Inst), Arrys Therapeutics (Inst), AstraZeneca/MedImmune (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Clovis Oncology (Inst), Exelixis (Inst), Genentech/Roche (Inst), Gilead Sciences (Inst), Merck (Inst), Novartis (Inst), Pharmacyclics (Inst), Seattle Genetics (Inst), and Xcovery (Inst). She also reports  uncompensated relationships with Genentech/Roche, Merck, and Takeda.

Gralow reports relationships with AstraZeneca, Genentech, Sandoz, and Immunomedics.

Piotrowska declares relationships with AstraZeneca, Blueprint Medicines, C4 Therapeutics, Eli Lilly, InCyte, Medtronic, Cullinan-Pearl, Novartis, Spectrum, Takeda, and Tesaro (All to institution).

American Society of Clinical Oncology Annual Meeting: Abstract 8500. To be presented June 6, 2021.

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