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Key Studies in NSCLC: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Zofia Piotrowska, MD, MHS
Karen L. Reckamp, MD, MS
Released: August 20, 2021

Advances in Early-Stage NSCLC

IMpower010: Study Design

Karen L. Reckamp, MD, MS:
As shown in the phase III ADAURA trial, adjuvant osimertinib in patients with resectable early-stage NSCLC following standard adjuvant chemotherapy confers a substantial DFS benefit to those with EGFR-activating mutations, which led to the approval of osimertinib in this setting.1,2 However, patients with early-stage NSCLC lacking EGFR mutations still face a high unmet need for improved neoadjuvant/adjuvant approaches, and based on our success in unresectable, stage III and metastatic disease, immunotherapy is now being evaluated for this purpose.

IMpower010 is the first randomized phase III trial using immunotherapy in the adjuvant setting to read out.3 This study evaluated atezolizumab vs BSC following adjuvant chemotherapy in patients with stage IB-IIIA NSCLC after resection. One interesting point is that the primary endpoint followed a hierarchical evaluation of DFS in 3 different populations. The first group included patients with stage II-IIIA disease and PD-L1 tumor cell (TC) expression ≥1%. The second group was all randomized stage II-IIIA patients, and the third group was the intent-to-treat population of stage IB-IIIA patients. Secondary endpoints included OS and DFS in stage II-IIIA patients with PD-L1 TC ≥50%, 3-year and 5-year DFS, and safety.

IMpower010: Baseline Characteristics

Karen L. Reckamp, MD, MS:
Baseline characteristics were largely equivalent between the 2 arms by stage and in patients with stage II-IIIA disease and PD‑L1 TC ≥1%.3 The breakdown for patients with PD‑L1 TC 1% to 49% or ≥50%, which would be beneficial to see, was not presented.

IMpower010: DFS in Stage II-IIIA NSCLC With PD-L1 TC ≥1%

Karen L. Reckamp, MD, MS:
Median DFS in the initial population of stage II‑IIIA patients with PD‑L1 TC ≥1% was improved by atezolizumab vs BSC (median DFS: not estimable vs 35.3 months; HR: 0.66; P = .004). With a median follow-up of 32.8 months, the 3-year DFS rate was 60.6% with atezolizumab and 48.2% with BSC.3

IMpower010: DFS in Stage II-IIIA NSCLC With PD-L1 TC ≥1% Across Key Subgroups

Karen L. Reckamp, MD, MS:
Looking at the forest plot for DFS in this specific population with stage II‑IIIA disease and PD‑L1 TC ≥1%, we see a benefit for atezolizumab across most subgroups, with some outliers.3 The benefit with atezolizumab for patients with an Eastern Cooperative Oncology Group performance status of 1, squamous cell carcinoma, or N0 disease was notably less marked, with their HRs edging toward 1. The presence of an EGFR mutation also does not seem to impart a significant benefit with atezolizumab compared with BSC, and patients with ALK rearrangements seem to lack any benefit from atezolizumab, although the patient numbers in these groups are small. Of interest, current smokers are the most skewed toward potential benefit from BSC.

IMpower010: DFS in All Randomized Stage II-IIIA NSCLC

Karen L. Reckamp, MD, MS:
Moving on to the second group in the statistical hierarchy—all randomized patients with stage II‑IIIA disease—we still see a significant improvement in DFS with atezolizumab (median DFS: 42.3 months vs 35.3 months; HR: 0.79), albeit smaller in magnitude, but it did still cross the significance boundary (P = .02).3 The 3-year DFS rate was 55.7% with atezolizumab and 49.4% with BSC.

IMpower010: DFS in All Randomized Stage II-IIIA NSCLC Across Key Subgroups

Karen L. Reckamp, MD, MS:
In the subgroup analysis of all randomized patients with stage II‑IIIA disease, there is still a trend toward benefit in the atezolizumab arm. However, the HRs are much closer to the middle line across the board, as the benefit from atezolizumab was smaller in all randomized patients overall.3 HRs for patients with an EGFR mutation or ALK rearrangement trend toward 1. Looking at PD‑L1 status, patients with PD-L1 TC <1% derive the least benefit from atezolizumab, whereas patients with PD-L1 TC ≥50% derive the most benefit. Again, I would have liked to see a breakout of patients with PD-L1 TC 1% to 49%.

IMpower010: DFS in ITT Population (Stage IB-IIIA NSCLC)

Karen L. Reckamp, MD, MS:
In the intent-to-treat population with stage IB-IIIA disease, DFS did not cross its significance boundary, so they will continue to do follow-up past the interim analysis. At 3 years, the DFS rate was 57.9% in the atezolizumab arm and 52.6% in the control arm.3

IMpower010: Early OS

Karen L. Reckamp, MD, MS:
OS data are immature and not formally tested at this interim DFS analysis. It is too early to tell whether there is an OS benefit with atezolizumab in any of the patient populations analyzed.3

IMpower010: Safety

Karen L. Reckamp, MD, MS:
Safety outcomes were similar to those observed in prior studies with atezolizumab as monotherapy. Grade 3/4 TRAEs were approximately 10% in the atezolizumab arm, serious TRAEs were 7.5%, and grade 5 TRAEs were <1%.3 Adverse events (AEs) with atezolizumab led to dose interruption in close to 30% of patients and discontinuation in <20% of patients.

IMpower010: Immune-Mediated AEs Occurring in ≥1% of Patients

Karen L. Reckamp, MD, MS:
Looking at immune‑mediated AEs, again we see what is generally expected with atezolizumab. Of note, grade 3/4 pneumonitis was not significantly elevated (<1%) in the atezolizumab arm.3

IMpower010: Clinical Implications

Karen L. Reckamp, MD, MS:
Dr. Piotrowska, I’m interested to hear your thoughts on IMpower010 and the potential to use immunotherapy in the adjuvant setting for the treatment of our patients with resectable, early-stage NSCLC.

Zofia Piotrowska, MD, MHS:
IMpower010 is an important study in that it is the first look at adjuvant immunotherapy for lung cancer. Based on the benefits seen in the settings of unresectable stage III and metastatic disease, we all have been really interested in looking at immunotherapy in the adjuvant setting. There also is a tail on the survival curve with immunotherapy for some patients with metastatic disease, suggesting durable benefit. We all agree that there is a real potential here for adjuvant immunotherapy to have benefit in terms of improving cure in the setting of early-stage disease. Overall, I was impressed with the data, although it is an early look and there is more to learn. But I was encouraged to see the improvement in DFS, particularly in the PD‑L1–positive population.

One of the most interesting findings was looking at the breakdown by PD‑L1 status and the magnitude of benefit in the PD-L1 TC ≥50% population. There is discussion as to whether that’s really the population driving the benefit in this study, and I agree it would be helpful to see a breakdown of PD-L1 TC 1% to 49% vs ≥50%, as you mentioned. But overall, I was certainly impressed with these data for the PD‑L1–positive patients, and I anticipate and hope that atezolizumab will receive FDA approval for adjuvant treatment.

Karen L. Reckamp, MD, MS:
I agree with you. It’s exciting to see patients with long‑term responses, like in the metastatic setting, and it may lead to more cures in the early stage setting. Although DFS does not always correlate with OS—and we of course want to see an OS benefit—I’m encouraged by what we see in the metastatic setting, which generally is that when we see PFS benefit, we also see OS benefit. We’ve even seen OS benefit with immunotherapy without PFS benefit in the metastatic setting, so I’m encouraged by these data. I am willing to utilize DFS data with immunotherapy probably even more so than with targeted therapy to guide my treatment recommendations in early-stage disease.

I also agree that looking across PD‑L1 expression levels will be important—in particular the data for those with PD-L1 TC 1% to 49%. If atezolizumab had FDA approval, I would likely give it to my patients with PD-L1 TC ≥50% and would avoid using it in patients with PD-L1–negative disease.

Zofia Piotrowska, MD, MHS:
The question of DFS vs OS is such an interesting one, and I agree that it’s likely different for the immunotherapy studies than for the TKI studies. Extrapolating from the unresectable stage III setting, we initially saw PFS benefit with immunotherapy that then did translate into OS benefit, and I’m hopeful that will be the case here, too. Numerous other similarly designed studies are ongoing—the majority of which also have DFS as the primary endpoint—that we hope will read out in the near future. As a community, we have to feel comfortable using DFS to guide our practice if that’s how the studies are being designed. It will be helpful to see the results of these other studies as corroboration to IMpower010. I anticipate that, over the coming months and years, we will be using immunotherapy as adjuvant therapy in our patients with PD‑L1–positive early-stage NSCLC.

Karen L. Reckamp, MD, MS:
What do you think about the use of neoadjuvant immunotherapy or immunotherapy/chemotherapy combinations?

Zofia Piotrowska, MD, MHS:
The neoadjuvant approach looks promising. Recently, we’ve seen really nice improvements in major and complete pathologic response in the CheckMate 816 study evaluating neoadjuvant nivolumab plus chemotherapy or nivolumab/ipilimumab vs chemotherapy alone in stage IB-IIIA NSCLC.4 The question really will be, first of all, do pathologic endpoints translate into survival endpoints for the neoadjuvant studies? We don’t have the answer to that question. Ultimately, if immunotherapy trials in both settings are positive, we’re going to have to decide what our preference is between neoadjuvant and adjuvant immunotherapy. I think there are advantages to both, and I don’t know that there’s a clear winner in my mind. How do you view it?

Karen L. Reckamp, MD, MS:
With the CheckMate 816 study, I was impressed with the surgical outcomes presented this year at ASCO and the fact that more patients were able to have minimally invasive surgery and potentially lobectomy. The use of neoadjuvant therapy to minimize the tumor so the surgery may be more feasible or less aggressive is not generally a discussion we’ve had in lung cancer, but it may be something that immunotherapy can do for our patients, so I’m intrigued about using immunotherapy in the neoadjuvant setting. As a scientist, I like the questions we can ask in the neoadjuvant setting, but I also understand that, in many ways, the adjuvant setting is often where we capture these patients and are able to give them the therapy they need.

Zofia Piotrowska, MD, MH
Ultimately, maybe the 2 strategies won’t be mutually exclusive. Maybe we will have an approach where we start with a neoadjuvant immunotherapy or chemotherapy/immunotherapy strategy, and then we can measure the magnitude of benefit at the time of surgery and potentially tailor our approach in terms of adjuvant therapy, as well. So I think in the end, we may end up using both strategies for some patients.

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