Neoadjuvant Immunotherapy Proving to Be Effective, Safe Option in Lung Cancer

Immunotherapy prior to surgery can be employed safely and effectively for patients with lung cancer, said Erin A. Gillaspie, MD, MPH. Checkpoint inhibitors are often used in the advanced stage, but she argued during a presentation at the 19th Annual Winter Lung Conference^® that the data show physicians should consider utilizing this class of agents earlier in treatment.¹

“Surgery actually can be performed very safely after the treatment with immunotherapy,” said Gillaspie, assistant professor of thoracic surgery at Vanderbilt-Ingram Cancer Center. “Now we start seeing transitioning out of salvage and into the intentional use of immunotherapy in the neoadjuvant setting.”

She noted that there is established evidence in diseases such as colorectal cancer, renal cell carcinoma, and melanoma that neoadjuvant immunotherapy and targeted therapy are associated with positive outcomes. Neoadjuvant treatment reduces burden of disease, eliminates microscopic disease sites, and primes the immune system against tumor cells.

“The other thing that we see also is a higher compliance rate,” Gillaspie added. “Some people think of it as we’re holding the carrot out. A lot of patients really want to get to surgery, so they know that to be able to get to surgery, they have to go through this therapy. We’re seeing a much higher rate of completion.”

There is strong recent data supporting neoadjuvant immunotherapy in lung cancer. In 2020, Spanish investigators published data from the open-label, multicenter, single-arm phase 2 NADIM trial (NCT03081689). From August 2017 to August 2018, 46 patients with treatment-naïve stage IIIA non–small cell lung cancer (NSCLC) received neoadjuvant treatment prior to surgery at 18 hospitals.

Patients received 200 mg/m² paclitaxel and carboplatin (area under the curve 6 mg/mL per minute) plus 360 mg nivolumab (Opdivo) on day 1 of each 21-day cycle for 3 cycles before surgical resection. They then received adjuvant single-agent nivolumab at 240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months. The primary end point was progression-free survival (PFS) at 24 months.²

The median duration of follow-up was 24.0 months (interquartile range, 21.4-28.1). At the time of the January 31, 2020, data cutoff, 35 of 41 patients who had tumor resection were progression free. The 24-month PFS rate was 77.1% (95% CI, 59.9%-87.7%).

Forty-three of the 46 patients (93%) had treatment-related adverse events (TRAEs) during neoadjuvant treatment; and 14 (30%) had TRAEs events of grade 3 or higher. However, investigators concluded that none of the AEs were associated with surgery delays or deaths. The most common grade 3 or higher TRAEs were increased lipase (7%) and febrile neutropenia (7%).

“[Investigators] were able to accomplish an R0 resection in 100% of their patients. They had an unprecedented major pathologic response in about 85% of their cases,” she said. “They were able to show that they had an appropriate and equivalent perioperative morbidity mortality to what we would expect in other patients undergoing comparable surgery. Again, we’re showing safe and efficacious treatment in the neoadjuvant setting.”

Findings from the phase 3 CheckMate-816 trial (NCT02998528) presented at the 2021 ASCO Annual Meeting show similar results with neoadjuvant therapy.

Investigators enrolled 358 patients with newly diagnosed, resectable, stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1 and no known sensitizing EGFR mutations or ALK alterations. Participants were stratified by disease stage (IB/II vs IIIA), PD-L1 expression (≥ 1% vs < 1%), and sex (male vs female).³

Patients were randomly assigned to 360 mg nivolumab every 3 weeks plus chemotherapy (n = 179) or chemotherapy alone for 3 cycles (n = 179). Those in the investigative arm who had nonsquamous disease received pemetrexed plus cisplatin or paclitaxel and carboplatin, and those with squamous disease were given gemcitabine plus cisplatin or paclitaxel and carboplatin.

Patients in the control arm received vinorelbine plus cisplatin, docetaxel plus cisplatin, gemcitabine plus cisplatin if they had squamous disease, pemetrexed plus cisplatin if they had nonsquamous disease, or paclitaxel plus carboplatin.

Patients then underwent surgery within 6 weeks after treatment. They then received adjuvant chemotherapy with or without radiation. Lastly, they underwent follow-up.

The rate of pathologic complete response (pCR) with nivolumab plus chemotherapy was 40% vs 0% with chemotherapy alone among those with stage IB disease. The pCR in the investigative and control arms were 23% vs 3%, respectively, in those with stage IIA disease. In those with stage IIB disease, the pCRs were 24% vs 9%, respectively, and in those with stage IIIA disease, these rates were 23% vs 1%, respectively. Investigators noted an improvement in pCR was in the combination arm irrespective of radiologic downstaging.

The median residual viable tumor percentage in patients with stage IB/II and IIIA disease was 28% and 8%, respectively, with nivolumab plus chemotherapy, vs 79% and 70%, respectively, with chemotherapy alone.

R0, R1, and R2 rates of resection were found to be comparable irrespective of baseline disease stage in both arms. The median number of lymph nodes dissected also proved to be similar between the arms and length of hospital stay was also comparable irrespective of disease stage at baseline.

Surgery was delayed in 21% of those on the nivolumab arm vs 18% of those on the chemotherapy-alone arm. The length of delay was 2.0 weeks (range, 0.6-3.0) vs 2.4 weeks (range, 1.0-3.7), respectively.

Investigators observed 41 any-grade AEs in the experimental arm vs 47 in the chemotherapy-alone arm. Eleven patients in the experimental arm and 15 in the control arm experienced grade 3/4 toxicities. Gillaspie noted that there were comparable rates of perioperative morbidity and mortality.

“Not only are we able to deliver this in a neoadjuvant way effectively; it’s not impeding the feasibility of surgery at all,” she said. “Patients are not having a side effect profile that's preventing them to go onto surgery, but it might actually be enhancing our ability to perform a surgery, which is sort of exciting as we see this data coming.”

References

1. Gillaspie EA. Is surgery safe after neoadjuvant IO? Is IO safe after surgery? Presented at: 19th Annual Winter Lung Cancer Conference; February 4-6, 2022; Miami, FL. Accessed February 5, 2022.
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. 2020;21(11):1413-1422. doi:10.1016/S1470-2045(20)30453-8.
3. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503.