Neoadjuvant Atezolizumab Followed by Adjuvant Atezolizumab May Benefit Select Patients With Early-stage NSCLC

Karen L. Reckamp, MD, MS

Data from an exploratory analysis of the phase 2 LCMC3 trial (NCT02927301) suggest that patients with resectable stage IB to IIIB non–small cell lung cancer (NSCLC) who received adjuvant atezolizumab (Tecentriq) after neoadjuvant atezolizumab and surgical resection may have experienced an improvement in disease-free survival (DFS) and a trend toward improved overall survival (OS) vs those who did not receive adjuvant treatment.¹

Prior data from the trial showed that patients who received neoadjuvant atezolizumab after surgery (n = 143) had a major pathological response (MPR) rate of 20% (95% CI, 14%-28%), and a 3-year OS rate of 80% when they received neoadjuvant atezolizumab following surgery.²

Findings from the exploratory analysis were presented during the 2023 AACR Annual Meeting and showed that of the 137 MPR-evaluable patients, 29 had a MPR. Those who received adjuvant atezolizumab after neoadjuvant therapy and resection (n = 53) experienced a 3-year DFS rate of 83% vs 64% in those who did not receive adjuvant treatment (n = 84; HR, 0.44; 95% CI, 0.21-0.91). Moreover, at a median follow-up of 3.1 years, the 3-year landmark OS rates were 89% and 77%, respectively (HR, 0.48; 95% CI, 0.19-1.21).¹

“[Regarding] the future of immunotherapy in NSCLC, we now know that adjuvant therapy benefits certain patients following resection and standard chemotherapy. We [also] know that neoadjuvant therapy, especially [when administered] with chemotherapy, benefits a subset of patients who undergo surgical resection,” lead study author Karen L. Reckamp, MD, MS, told OncLive^®. “The question is, in those patients who receive neoadjuvant therapy, who are the ones who will benefit from further adjuvant therapy? This study helps to lay the groundwork that there is some benefit to be seen [with this approach] but [future studies will be needed] to identify who those patients are.”

In the interview, Reckamp, discussed the rationale for evaluating patients with early-stage NSCLC who received adjuvant atezolizumab as part of the LCMC3 study and explained the significance and limitations of data from a retrospective analysis.

Reckamp is a professor of medicine, director of the Division of Medical Oncology and Lung Institute at Cedars-Sinai Medical Center and an associate director of Clinical Research at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, in Los Angeles, California.

OncLive^®: Please provide some background on the phase 2 LCMC3 study. What was examined and what data have previously been reported?

Reckamp: The LCMC3 study was an evaluation of neoadjuvant atezolizumab in patients with early-stage, resectable NSCLC. In this study, all participants received neoadjuvant therapy. The results of this have been published and presented. The study met its primary end point of a MPR rate of more than 20% in those patients who received neoadjuvant therapy.

A portion of patients in the study also received adjuvant atezolizumab; that was an option in the study. This analysis looked at those patients who received the optional [adjuvant] atezolizumab for [up to] 1 year and evaluated [their] outcomes [in comparison with] those who did not end up receiving the adjuvant atezolizumab. Notably, these patients may be different, and there may be reasons why they didn’t receive the adjuvant therapy. [Still,] this gives us some perspective in a prospective way.

Did any other studies support the inception of this particular analysis? What unmet needs might this research address?

We now have an FDA approval with [data from] the [phase 3] CheckMate-816 trial [NCT02998528] using chemotherapy and nivolumab [Opdivo] as neoadjuvant therapy. In that study, patients had an improvement in disease-free survival when they received chemotherapy and immunotherapy compared with chemotherapy alone in the neoadjuvant setting.

Adjuvant immunotherapy was not a part of the trial [design], and the trial was conducted prior to the approval of adjuvant immunotherapy [in NSCLC]. These studies [do not really provide an] understanding of who should receive that adjuvant therapy; [therefore], further understanding is needed.

There are several unmet needs in resectable NSCLC and the use of neoadjuvant and adjuvant therapy, or perioperative therapy as both neoadjuvant and adjuvant therapy. The caveat is that this is a retrospective analysis of a subset of patients who were not randomized to receive adjuvant immunotherapy or not. [Bearing that in mind], this [analysis] does shed some light on the importance of adjuvant immunotherapy, specifically atezolizumab, in patients who also received neoadjuvant therapy.

Could you expand on the trial design and the patient population enrolled?

LCMC3 was a single-arm, open-label, multicenter phase 2 trial using neoadjuvant atezolizumab followed by surgical resection and then optional adjuvant atezolizumab for patients who have early-stage resectable NSCLC. Patients had to have stage IB to IIIA NSCLC, [although some] patients with stage IIIB resectable NSCLC [were included]. They had to have measurable disease and [must have] received 2 cycles of neoadjuvant atezolizumab prior to surgery. All patients were offered the option to receive standard-of-care [SOC] adjuvant chemotherapy.

When we did this trial, adjuvant chemotherapy was the SOC with or without radiation as per the investigator’s [discretion]. In addition, those who experienced some clinical benefit from neoadjuvant therapy [according to] the investigator’s [assessment] and the results of the surgery and imaging, could receive up to 1 year of adjuvant atezolizumab.

​​What were the findings from the analysis presented at the 2023 AACR Annual Meeting?

The [follow-up] results presented at the AACR Annual Meeting, [were the] 3-year DFS rates in the 137 patients who were [response] evaluable. In this patient population, we had a 3-year DFS [rate] of 72% at a median duration of follow-up of 3 years. This is impressive in a group of patients with stage I to III disease. The 3-year OS [rate] for this population was 82% with a median duration of follow-up of 3.1 years. These are exciting data.

Subsequently, we specifically evaluated patients who received the adjuvant atezolizumab vs those who did not. About two-thirds of the patients did not receive adjuvant atezolizumab and about one-third did. With 3 [years of] follow-up, we do see a benefit for patients who received adjuvant atezolizumab in addition to neoadjuvant atezolizumab. Again, this was not a randomized, controlled arm, and there may be other reasons for that [outcome].

Were any new safety signals identified in this analysis?

The safety [profile] was as expected. We did see immune-related adverse effects [AEs]. [Twenty-one percent] of those who received adjuvant atezolizumab had grade 3/4 treatment-related AEs [TRAEs]. There were no grade 5 TRAEs [observed] in this [analysis]. As we would expect, there is some additional toxicity seen with that additional benefit.

What next steps are planned for this research? What should your colleagues take away?

The LCMC3 study has [supported the launch of the] LCMC4 study [NCT04712877], which is currently evaluating neoadjuvant targeted therapies for patients with resectable NSCLC.

We know that PD-1 and PD-L1 inhibitor therapy is beneficial for patients in the perioperative setting. It should absolutely be utilized for most patients in this setting, except possibly those with EGFR mutations or other targeted alterations. [Additional studies will be needed to help us to understand] whether [patients who] use it in the neoadjuvant setting will benefit in the adjuvant setting. However, the ability to look at responses in the neoadjuvant setting for [patients] who may have residual disease could help us to know whether using [this approach] in the adjuvant setting will be [beneficial]. Therefore, patient selection will be important when we use [immunotherapy] across the perioperative setting.

What other presentations were you excited to see presented at this year’s meeting?

The clinical research being presented at AACR is exciting and helps us to identify new therapies for our patients. The [phase 3] AEGEAN study [NCT03800134] was presented at [the meeting] and is the first to look at perioperative durvalumab [Imfinzi] with neoadjuvant chemotherapy. This study did have adjuvant immunotherapy [as an option] and it met its end points of MPR rate and DFS. [This serves as] more evidence that perioperative immunotherapy both pre- and post- [surgery] may be important for patients with resectable NSCLC.

Disclosure: Dr Reckamp reports working as an independent contractor for Mirati, Genentech, Blueprint, Calithera, Daiichi Sankyo, Elevation Oncology, Janssen, Amgen, AstraZeneca, EMD Serano, GSK, Merck, Seattle Genetics, and Takeda; she reports receiving institutional support from Mirati, Genentech, Blueprint, Calithera, Daiichi Sankyo, Elevation Oncology, and Janssen.

References

1. Carbone DP, Waqar SN, Chaft JE, et al. Efficacy and safety of adjuvant (adj) atezolizumab (atezo) from the Phase 2 LCMC3 study. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, Florida. Abstract CT215.
2. Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nat Med. 2022;28(10):2155- 2161. doi:10.1038/s41591-022-01962-5