Updated 5-Year Data From the IMpower010 Trial

Jamie Chaft, MD, Memorial Sloan Kettering Cancer Center, New York, New York, shares insights on the 5-year update to the IMpower010 trial, evaluating adjuvant atezolizumab for patients with resectable stage II to IIIA non-small cell lung cancer compared with best supportive care. This updated data found atezolizumab continued to provide greater improvement to disease-free survival for this patient population, regardless of disease stage or regional lymph node status.

Dr Chaft concluded that the updated data were “very reassuring.” Going on, she said, “They reaffirm our clinical practice of prescribing new checkpoint inhibitors in patients with resected EGFR and ALK wild-type tumors that are of high enough risk to justify such therapy, and particularly those with PD-L1–positive or PD-L1–high disease”

Read more about the updated IMpower010 data here.

Transcript:

Hi, Jamie Chaft. I'm a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center.

What was the treatment landscape for resectable early-stage non-small cell lung cancer, prior to atezolizumab?

The treatment of surgically resectable early stage non-small cell lung cancer really didn't change for over 20 years. The standard of care was upfront surgical resection for patients with localized or regionally advanced non-small cell lung cancer, followed by adjuvant cisplatin-based chemotherapy. And no trial, up until the era of immunotherapy and targeted therapy, really changed that standard of care.

In the last few years, first the targeted therapy but more recently with immunotherapy, we've seen that landscape shift. And we now have FDA approvals in the United States for checkpoint inhibitors, PD-1 or PD-L1 drugs, in patients with resectable non-small cell lung cancer without EGFR and ALK alterations.

What were the results and impact of the IMpower010 trial?

The first study to change the standard of care in a large population of patients was IMpower010. This study was very rigorously done in a patient population with resected non-small cell lung cancer who was fit enough for what was the standard of care, and that's adjuvant cisplatin-based therapy. This study was done in the seventh-edition staging system. At that time, they enrolled patients that tumors that were 4 cm or larger or lymph nodes involved with the cancer at the time of surgery. After completing standard adjuvant cisplatin-based chemotherapy, they were randomized to atezolizumab, a PD-L1 antibody, or best supportive care for up to a year.

The study had a fairly fancy, hierarchical statistical design, looking first at the population of patients most likely to benefit: that’s patients with stage 2 and 3 lung cancer whose tumors express PD-L1. Followed by all patients with stage 2 or 3 resected lung cancer. And then their third shot on goal there was including the smaller tumors that were 4-to-5 centimeters or what was historically 1B. Their fourth statistical hit would have been overall survival if the first 3 were positive, and these are the updates we saw most recently at World Lung.

The high-level data initially was that patients clearly had a benefit in terms of disease-free survival advantage with adjuvant atezolizumab after cisplatin-based chemotherapy, if they had a resected stage 2 or 3 tumor with high PD-L1 expression. The study was positive for the patients with PD-L1–positive tumors, and that is where the FDA indication is. For all patients in the intention-to-treat analysis with stage 2 and 3, there was also an advantage. However, that was clearly driven by tumors with PD-L1 expression.

What was the updated data seen at the 2024 World Conference on Lung Cancer?

At World Lung, we saw a very mature 5-year update of the IMpower010 data, which did not have a formal testing of the overall survival (OS) hypothesis — that’s what a lot of the hold-outs are still waiting for. I'm not sure if we'll get there, with their complex design. But we did see some really interesting data, clearly showing an ongoing benefit for disease-free survival in patients with stage 2 and 3, PD-L1–high tumors without EGFR and ALK alterations. And I don't think that surprised anyone, but it's certainly reassuring. We also saw updated data on the patterns of recurrence in patients who did recur.

I think my takeaway here, again, not surprising, but really telling us what we knew, but what we need to do more future research on, and that is the adequacy of surgery. We saw that the adjuvant atezolizumab did a great job of reducing distant recurrence. However, for patients with what I have to assume was incomplete surgery, they are with a retained risk of locoregional relapse. So, perhaps we need to reinvestigate post-operative radiotherapy, an art that has really been put aside lately, and take a much closer look at the adequacy of nodal resection and surgical margins in our future studies.

I don't have any insider data as to whether we'll ever get to see that overall survival readout. The way the statistics, as I understand them, are they first must cross a significant threshold in the intention-to-treat (ITT) population prior to moving on to OS. And that ITT includes smaller tumors, so patients at lower risk of relapse, therefore, the bar to reach statistical significance in that overall population is higher. I'm not sure if we'll see formal testing of OS, but the trends that we have seen are certainly reassuring.

What are the impact of these updated results?

To summarize the updated data, I would say that they're very reassuring. They reaffirm our clinical practice of prescribing new checkpoint inhibitors in patients with resected EGFR and ALK wild-type tumors that are of high enough risk to justify such therapy, and particularly those with PD-L1–positive or PD-L1–high disease. And that we need to be sure before prescribing these adjuvant therapies that our patients have had the best surgery to prevent locoregional relapse as a failure where perhaps these immunotherapies by themselves are not going to salvage.

What do you think future research should focus on?

I think in the future we have to look a little more broadly and really begin to personalize our cancer therapies. The IMpower010 in my eyes had a flaw of originally enrolling patients with EGFR- and ALK-positive disease, as did some of the other adjuvant studies. We know, and knew then, that these patients don't benefit from these drugs and have highly-effective targeted therapies.

Non-small cell lung cancer is not one disease, it is a constellation of many different subtypes of lung cancer, and we have to begin to look at these subtypes individually, particularly if we're doing an adjuvant study where that time is not of the essence. We can do next generation sequencing on all these patients and get much better insight into who truly should and should not receive these adjuvant therapies.

I would probably be remiss not to also to other technologies such as circulating tumor (ct) technologies, whether it's ctDNA or other evolving techniques. But we hopefully will have the opportunity in the future not only to escalate in patients of higher risk, but also to de-escalate therapy in patients who don't need additional treatment after surgery.

Source:

Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5.

Felip E, Wakelee HA, Vallieres E, et al. IMpower010 5-y subgroup analysis and relapse patterns: Phase 3 study of atezolizumab vs BSC in stage II-IIIA NSCLC. Presented at 2024 IASLC WCLC; September 7-10, 2024. San Diego, California.