乌鸦传媒

The 2020 results from the phase II NADIM trial set the stage for the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable, stage IIIA non-small cell lung cancer (NSCLC).

At the time, Mariano Provencio-Pulla, MD, PhD, of the Instituto Investigacion Sanitaria Puerta de Hierro-Segovia de Arana, Hospital Universitario Puerta de Hierro-Majadahonda, in Madrid, and colleagues advanced the idea of chemoimmunotherapy as the star of the show: "Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable," they wrote in the.

More recently the group also reported 3-year results in the for overall survival and circulating tumor (ct)DNA biomarker analysis.

First, the researchers noted that at the time of the March 2021 data cutoff, disease progression was seen in 12 of 46 patients, and nine deaths were recorded. Three of the deaths were in patients who did not have surgery but did not have disease progression, while four were in patients who had surgery and disease progression. There were two deaths in patients who were deemed disease-free post-surgery, but who died of COVID-19.

"The median PFS [progression-free survival] and the median OS [overall survival] were not reached in the ITT [intention-to-treat] or PP [per-protocol] population. The median time to progression for patients who had progressive disease was 19.4 months," the investigators stated, adding that OS in the ITT population was 81.9% at 36 months and 78.9% at 42 months, while it came in at 91.0% (95% CI 74.2 to 97.0) and 87.3%, respectively, in the PP population.

As for the biomarker analysis, based on 43 pre-treatment plasma samples, the authors reported that PD-L1 expression in tumor cells was not linked with improved PFS or OS, and that tumor mutational burden assessment was not associated with survival outcomes.

However, baseline ctDNA was detected in 69.8% of the samples, and these levels at baseline were significantly associated with tumor size. Patients with ctDNA levels <1% mutant allele fraction at baseline had significantly better PFS and OS versus patients with high ctDNA levels (adjusted HR 0.20 for PFS; adjusted HR 0.07 for OS). And improved PFS and OS were seen for patients with undetectable ctDNA after neoadjuvant treatment (adjusted HR 0.26 for PFS; adjusted HR 0.04 for OS).

Some of these findings were presented at the 2021 World Conference on Lung Cancer and at that time NADIM co-investigator Atocha Romero, PhD, of the Hospital Universitario Puerta De Hierro in Madrid, told that ctDNA predicted survival better than tumor response on CT scans and according to RECIST criteria -- "so ctDNA clearance is indeed a good prognostic factor and can be validated as a surrogate for long-term survival in these patients."

The primary results from phase II NADIM showed that patients who received pre-surgical neoadjuvant treatment with IV paclitaxel and carboplatin plus nivolumab, followed by post-surgical adjuvant IV nivolumab monotherapy for 1 year, achieved a PFS of 77.1% at 24 months.

Provencio-Pulla shared more on those results in a presentation at this year's , while ASCO discussant and thoracic surgeon Jessica Donington, MD, of the University of Chicago Medical Center, offered her take on the NADIM results and their potential impact on treatment moving forward.

What is the background for the phase II NADIM study?

Provencio-Pulla: Approximately 20% of patients are diagnosed as stage IIIA N2 affectation. This is a complex scenario which requires teamwork. The prognosis is poor. And when patients have N2 affectation, there is usually micrometastatic disease. And even with all multimodal treatments, we have only 30% overall survival at 5 years.

Preoperative chemotherapy has been shown to significantly improve overall survival, and there is a strong association between pathological complete response [pCR] and survival following neoadjuvant chemotherapy. However, the median pCR after neoadjuvant chemotherapy is very low, around 5%.

Neoadjuvant immunotherapy or immunochemotherapy for NSCLC has some promising activity in several single-arm phase II trials. saw a higher pCR and higher EFS [event-free survival] compared with neoadjuvant chemotherapy.

Donington: We see , proof of concept, the confirmation of the results with CheckMate 816, and now a validation with a second prospective randomized trial [phase II NADIM].

What about patient characteristics, particularly in terms of surgery?

Provencio-Pulla: [In phase II NADIM], 86 patients were included -- 57 in the experimental arm, 29 in the control arm. Baseline characteristics showed no statistically significant differences between the two arms. Remarkably ... almost 72% in the nivo-plus-chemo arm had N2 affectation. And half of them had multiple stations.

Regarding surgery, 93% of patients underwent surgery versus 69% in the control arm [odds ratio 5.96, P=0.008]. In four patients ... the surgery was canceled in the nivo-plus-chemo arm -- one due to adverse events and three not suitable for surgery. In nine patients, the surgery was canceled in the control arm -- four due to disease progression and five not suitable for surgery after evaluation by a multidisciplinary team.

What about the pCR results?

Provencio-Pulla: The primary endpoint, pCR, was higher in the experimental arm -- 36.8% versus 6.9% [OR 7.88]. A secondary endpoint, mPR, major pathological response, was 52.6% in the experimental arm, 13.8% in the control arm [OR 6.94]. Patients who achieved pCR had higher PD-L1 expressions than patients who did not.

What is the take-home message from the phase II NADIM?

Provencio-Pulla: NADIM II confirms superiority of neoadjuvant nivo-plus-chemo combination in patients with resectable stage IIIA-B. The addition of neoadjuvant nivo plus chemo significantly improved pCR, maintained safety profile, and did not impede the feasibility of surgery. And PD-L1 expression, a predictive value for pCR ... in our opinion, this should be the standard of care in these patients.

Where do NADIM findings fit into the larger treatment landscape of resectable stage IIIA NSCLC?

Donington: As one of the handful of surgeons in an [ASCO] auditorium full of medical oncologists, I'm going to ask about choice of cytotoxic therapy.

So one of the key differences between CheckMate [816] and the two NADIM trials was the chemotherapy. NADIM limited it to carbo/taxol [paclitaxel], while CheckMate allowed multiple regimens.

Given that the carboplatin patients maybe performed a little bit better in these trials, I am going to ask the question: Is carbo a better partner? Are we asking our cytotoxics to do something different in the terms of immune-modulating these tumors? And I don't have an answer, but I'm beginning to scratch my head here ... So their [phase II NADIM] conclusions was that this confirms the superiority of neoadjuvant nivo plus chemotherapy compared to chemotherapy alone with this significant improvement in [pCR].

Survival is actually still pending [at the time of the ASCO presentation]. My conclusions are now that we have three prospective trials using the same treatment and consistent pathologic responses and biomarker performance. I think this is very exciting.

Read the JCO study here and expert commentary about the clinical implications here.