Refining Adjuvant Immunotherapy Use Is a Crucial Focus in Early-Stage NSCLC

Although several pivotal trials have shown the benefit of perioperative immunotherapy in early-stage non–small cell lung cancer (NSCLC), particularly for patients with actionable driver mutations such as EGFR and ALK, further pragmatic studies are needed to address lingering uncertainties regarding the optimal use of adjuvant approaches in select patient subgroups, according to Kaushal Parikh, MBBS.

“The advent of immunotherapy really changed the landscape first in the metastatic setting and now in early-stage disease,” Parikh said in an interview with OncLive^® regarding a recent State of the Science Summit™ on lung cancer, which he chaired. “This is great because some of the best interventions that we can offer [are for] patients [identified] in the earliest stages…[However,] identifying patients who benefit from adjuvant immunotherapy if they have not achieved a great response following neoadjuvant immunotherapy is one of the needs of the hour. Right now, we don’t have an answer.”

Positive disease-free survival (DFS) and overall survival (OS) data from the final analysis of the phase 3 ADAURA trial (NCT02511106) proved the feasibility and efficacy of targeting EGFR mutations in the adjuvant setting for patients with early-stage, completely resected NSCLC, establishing the third-generation TKI osimertinib (Tagrisso) as a standard of care (SOC) in this setting.¹

Similar results were reported with adjuvant alectinib (Alecensa) in the phase 3 ALINA trial (NCT03456076). In the intention-to-treat (ITT) population, which comprised patients with stage IB to IIIA ALK-positive NSCLC, alectinib (n = 130) elicited a median DFS that was not reached (NR) vs 41.3 months (95% CI, 28.5-not evaluable) with chemotherapy (n = 127). Alectinib also reduced the risk of disease recurrence or death by 76% vs chemotherapy in the ITT population (HR, 0.24; 95% CI, 0.13-0.43, P < .0001). Based on these data, the FDA approved alectinib for use following surgical resection in this patient population in April, 2024.²

In the interview, Parikh highlighted the shift from traditional chemotherapy to immunotherapy-based combinations in early-stage NSCLC; emphasized the necessity of genetic testing to identify EGFR and ALK mutations prior to initiating neoadjuvant therapy; and posed several outstanding questions regarding the optimal use of adjuvant immunotherapy for this patient population based on PD-L1 status and pathologic responses.

Parikh is a thoracic oncologist and assistant professor of oncology at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: How has the availability of immunotherapy affected the management of early-stage NSCLC beyond traditional chemotherapy?

Parikh: We diagnose more patients with earlier stages of disease now, given that screening rates have somewhat improved compared with a few years ago. As this keeps happening, we will have more patients with earlier stages [of disease] diagnosed over the next few years. This is great, because some of the best interventions that we can offer [are for] patients [identified] in the earliest stages.

Surgery remains the mainstay of all curative-intent treatment. There are certain situations in which radiation can be prevalent. The major advances now are in the form of systemic therapies that we have to offer for patients with early-stage disease. For over 40 years, we only had platinum-based chemotherapies given either adjuvantly or neoadjuvantly as the SOC for patients who had resected tumors greater than 4 cm in size or with node positive disease. The advent of immunotherapy really changed the landscape first in the metastatic setting and now in early-stage disease as well.

Now, we also have 3 additional phase 3 studies in the US looking at perioperative chemoimmunotherapy. We have the KEYNOTE-671 trial [NCT03425643] of pembrolizumab [Keytruda] with platinum doublet chemotherapy given neoadjuvantly followed by surgery and adjuvant immunotherapy with pembrolizumab for 13 additional cycles to complete 1 year. Similarly, the AEGEAN trial [NCT03800134] and Checkmate-77T [NCT04025879] trials [are evaluating] durvalumab [Imfinzi] and nivolumab [Opdivo], respectively. These [regimens] are a significant improvement in what we offer to our patients before [surgery]. KEYNOTE-671 is the only study that has shown improvement in OS, and this has become a SOC for patients who have resectable early-stage NSCLC in the absence of EGFR/ALK alterations.

How have findings reinforced the importance of testing for EGFR and ALK mutations prior to neoadjuvant therapy?

When we look at patients with actionable driver [mutations], we have 2 phase 3 trials now: ADAURA [NCT02511106] and ALINA [NCT03456076], both showing improvements in DFS in patients with resected NSCLC with either EGFR or ALK alterations. [Results from] ADAURA read out a couple of years ago [showed] a significant improvement in DFS after adjuvant chemotherapy for patients with EGFR-positive NSCLC. More recently, OS data from this trial were presented in adult patients who were randomly assigned after surgery and chemotherapy to receive osimertinib or placebo. Three years of adjuvant osimertinib improved the 5-year OS rate by approximately 10% vs the placebo arm. This is a practice changing study. It also now mandates that patients receive EGFR and ALK testing, as well as next-generation sequencing in the early-stage setting before [the consideration of] immunotherapy.

ALINA is a similar study of adjuvant therapy with alectinib [Alecensa] vs chemotherapy. The 2 major differences between ALINA and ADAURA, apart from that one was in patients with EGFR mutations and the other was in those with ALK mutations, was that in ADAURA, patients were randomly assigned to receive osimertinib or placebo after chemotherapy. Although it was not mandatory, 60% of patients received [previous adjuvant] chemotherapy and 40% did not. In ALINA, patients were randomly assigned to receive either alectinib or chemotherapy.

The second major difference is that patients in ADAURA received osimertinib for 3 years, and those in ALINA received alectinib for 2 years. ALINA also met its DFS end point, and we saw that median DFS was not reached with alectinib whereas it was approximately 41 months with chemotherapy. When we look at landmark analysis, the 24-month DFS rate was 94% with alectinib vs 64% with chemotherapy. At 36 months, that difference was even greater. This is a practice-changing study, mandating that we test our patients for ALK fusions in the early stages.

With perioperative immunotherapy now considered SOC in resectable NSCLC, what questions still need to be answered to better leverage this approach?

Identifying patients who benefit with adjuvant immunotherapy if they have had a great response following neoadjuvant immunotherapy is one of the needs of the hour. Right now, we don’t have an answer. Here are the other questions in my mind about that. First, do we know whether patients with PD-L1–positive, –high, or –negative disease experience the greatest benefit with immunotherapy? Historically, patients who have PD-L1–high disease tend to experience the greatest benefit with immunotherapy. With that being said, all these perioperative chemoimmunotherapy regimens are available for patients regardless of PD-L1 expression.

Second, what about patients who achieve a pathologic complete response [pCR] vs those who do not? How are their outcomes different? pCR, major pathologic response, and DFS are essentially surrogates for OS, which is the main end point that we want for our patients. These studies, including the phase 3 CheckMate-816 trial [NCT02998528] and the first trials with nivolumab, looked at pathologic response and saw that patients who achieved a pathologic response had an improved DFS, and there was a strong signal for OS improvement. This was true regardless of the arm that patients were on. Patients who received chemotherapy alone and achieved a pCR also experienced a great improvement in DFS compared with those who did not achieve a pCR. Accordingly, there is a strong signal [supporting] pCR as a reasonable end point to achieve for these patients who receive adjuvant immunotherapy.

What is the added benefit of adjuvant immunotherapy in these patients who achieved a pCR? That is something that we don’t fully understand. What is the benefit of [added immunotherapy] for patients who have a major or minor pathologic response with the addition of immunotherapy? That is also something that we do not understand yet. We will need to design more pragmatic studies where we are able to escalate or deescalate treatment based on the pathologic responses or molecular responses seen in liquid biopsies, once we have more sensitive liquid biopsy assays.

In what scenarios would you use adjuvant immunotherapy in your practice?

The SOC is now to offer immunotherapy to all patients regardless of pathologic response. In my own practice, I prefer discussing adjuvant immunotherapy with all patients. The one situation in which I would not strongly recommend adjuvant immunotherapy is in patients who had significant residual disease, a minor pathologic response, or no pathologic response after 4 cycles of treatment. In this population, I would not be too keen on offering an additional 9 or 12 months of immunotherapy. However, for patients who achieve a major pathologic response, there is some benefit to extract from adjuvant immunotherapy. This is currently a data-free zone, and in patients who had a pCR, I’m not sure what immunotherapy adds anymore.

References

1. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
2. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA. April 18, 2024. Accessed July 31, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer