Chasing Survival Benefit With Novel Systemic Strategies in Early-Stage NSCLC

Kaushal Parikh, MD, MBBS

The use of chemoimmunotherapy and targeted therapy in the neoadjuvant and adjuvant treatment settings, respectively, has resulted in improvements in progression-free survival (PFS) and disease-free survival (DFS) in patents with early-stage non­–small cell lung cancer (NCLC), according to Kaushal Parikh, MD, MBBS. However, the question of whether these approaches will translate into an overall survival (OS) benefit remains unanswered.

“Several ongoing studies are evaluating the role of adjuvant and neoadjuvant immunotherapy in [patients with] early-stage lung cancer,” said Parikh. “For example, with the NADIM trial, we saw a higher rate of major pathological response [MPR]. We are still waiting to see whether this translates into a survival advantage, and thus, whether there is a use for immunotherapy in the neoadjuvant or adjuvant settings.”

In the phase 2 trial (NCT03081689), 46 adult patients with resectable NSCLC received neoadjuvant chemotherapy plus nivolumab (Opdivo). Results showed that the approach resulted in a MPR rate of 85% (95% CI, 71%-94%) and a complete pathologic response rate of 71% (95% CI, 54%-85%).¹ At a median follow-up of 24.0 months, the PFS rate was 77.1% (95% CI, 59.9-87.7).²

“In addition, we also saw data from the ADAURA trial, which showed a very impressive PFS advantage over placebo in patients with resected disease, following adjuvant chemotherapy,” added Parikh. “Again, although this is exciting, we still don't have evidence of an overall survival [OS] advantage yet. However, based on the [data] that we have so far, it seems appropriate to offer this to every patient that we see who has an EGFR activating mutation and IB/II/IIIA disease.”

Results from the phase 3 trial (NCT02511106) showed that adjuvant osimertinib (Tagrisso) resulted in a statistically significant improvement in DFS compared with placebo in patients with stage IB/II/IIIA EGFR-mutated NSCLC (HR, 0.17; 95% CI, 0.12-0.23; P <.0001).³ These data led to the December 2020 approval of osimertinib for use as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor certain EGFR mutations.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Parikh, a medical oncologist in the Thoracic Oncology and Phase I Clinical Trials Program at John Theurer Cancer Center, Hackensack University Medical Center, highlighted ongoing research exploring systemic approaches in early-stage NSCLC and shared where future efforts are headed.

OncLive®:What is the role of neoadjuvant chemoimmunotherapy in early-stage disease? Could you spotlight some of the findings from the NADIM trial?

Parikh: Based on the NADIM trial, along with some earlier studies, we have not been able to see any survival advantage. These have all been small, single-arm studies; none of them are randomized against neoadjuvant chemotherapy or adjuvant chemotherapy. We also have seen several adjuvant immunotherapy trials, which have not shown any survival or DFS benefit yet. It would be a little premature to offer this to our patients, outside of a clinical trial.

At Hackensack University Medical Center, we are primarily an adjuvant chemotherapy institution. It's very institution-dependent, whether up-front surgery or neoadjuvant chemotherapy will be used. At our institution, patients are typically taken to surgery first and then are considered for adjuvant treatment based on the surgical staging. There has never been a head-to-head comparison between neoadjuvant and adjuvant therapy; however, we know they are both better than no therapy at all. However, regarding neoadjuvant immunotherapy, we don’t have enough evidence to recommend it.

With regard to the adjuvant setting, the ADAURA trial generated a lot of excitement. Could you provide some background to this study?

ADAURA was a large study that evaluated patients with resected stage IB through IIIA disease. These patients received the standard of care and were subsequently randomized to receive 80 mg of osimertinib (Tagrisso) daily for 3 years or placebo. The primary end point of the trial was DFS, while the secondary end points were annual DFS, central nervous system [CNS] DFS, as well as OS and safety.

About 650 patients were accrued and about 240 were randomized to each arm. Most of the patients were female, as you would expect with EGFR-positive disease, and the majority were nonsmokers. Although most of the patients did receive adjuvant chemotherapy, about 45% of those in both arms did not. We also understand, from the baseline characteristics, that only about 30% of patients in each arm had stage IB disease. So, one question is, why did some not receive adjuvant chemotherapy? It seems like there were possibly some stage IIB and IIIA patients who did not receive any adjuvant chemotherapy, which is the standard.

What were the results reported with this approach? Are you offering this option to your patients despite the lack of OS data?

We knew that this was bound to be a positive study. We understand that osimertinib is the best-in-class TKI that we currently have for these patients. Results showed that the median DFS had not yet been reached for osimertinib versus about 20 months for placebo. The hazard ratio was 0.17, and the DFS [benefit] was seen across all stages.

Recently, during the 2020 ESMO Virtual Congress, CNS-DFS data were presented; this was found to also have been improved with osimertinib. If we further look at the subset analysis, every stage and every stratification factor criteria had improved DFS with osimertinib. The agent was superior for patients [irrespective of disease stage], whether they received adjuvant chemotherapy, of whether they had EGFR mutations or exon 19 deletions.

Also, the drug was well tolerated, as it always is. We know that some gastrointestinal and skin toxicities are associated with osimertinib, but we have ample experience with the drug; thus, we can offer it to patients. We now must determine whether this can be translated into an OS benefit; however, we know that this might take some time to figure out. Notably, this was a global study and the authors pointed out that upon progression, all patients on the control arm will be eligible to receive osimertinib. OS will be tough to [determine], but it’s also very important [to know]. Based on the DFS alone though, we should be offering this option, or at least discussing it, with our patients—especially for those with stage II or stage III disease.

Could you speak to some of the controversy surrounding this approach?

We have heard several conversations about the ADAURA trial after it was first presented during 2020 ASCO Virtual Scientific Program. Some argue the pros of this therapy, while others argue the cons. Many valid and legitimate points have been made. Every oncologist must ask their patients, along with their family members, whether they would like to receive adjuvant osimertinib.

Although I understand that this may not be a perfectly designed trial, with about 45% of patients not receiving the standard of care, which is chemotherapy, we don't know what percentage of these patients will end up receiving osimertinib upon progression. The trial was designed in a way that it would turn out positive. All that being said, we know that this is a good drug that is well tolerated, and it’s going to advance into an earlier line of treatment.

Where should future research efforts be focused?

Looking forward, I'm sure there will be trials looking at PD-1 and CTLA-4 inhibitors with or without chemotherapy. In the advanced setting, data from the CheckMate-9LA trial demonstrated that the combination of chemotherapy and immunotherapy does lead to improved survival. As such, this is something that I refer and recommend to patients frequently, especially since we can only administer 2 cycles of chemotherapy.

References

1. Provencio M, Nadal E, Insa A, et al. OA13.05 NADIM study: updated clinical research and outcomes. J Thorac Oncol. 2019;14(10):S241. doi:10.1016/j.jtho.2019.08.480

2. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. Published online September 24, 2020. doi:10.1016/S1470-2045(20)30453-8

3. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5