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Neoadjuvant nivolumab induces pathologic responses in advanced resectable non-small cell lung cancer
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CHICAGO — Neoadjuvant therapy with the anti-PD-1 therapy nivolumab induced responses among nearly half of patients with resectable lung cancer, according to study results presented at American Association for Cancer Research Annual Meeting.
The regimen also appeared safe and did not delay surgery.
“The most stunning finding was that nine of the 20 patients who had surgery after neoadjuvant anti-PD-1 had a major pathologic response,” researcher Drew Pardoll, MD, PhD, director of Bloomberg-Kimmel Institute for Cancer Immunotherapy and director of cancer immunology at Johns Hopkins School of Medicine, said in a press release. “Two patients had no evidence of viable cells in the resected specimen.
“This is particularly striking given that surgery was done, in most cases, just 4 weeks after the first dose of anti-PD-1 treatment,” Pardoll added. “Our result of a 45% major pathologic response rate is very encouraging, considering prior studies showing that a major pathologic response after neoadjuvant chemotherapy in lung cancer is associated with long-term survival.”
Perioperative chemotherapy is recommended for patients with resectable stage Ib to stage IIIb NSCLC, with 5-year survival rates ranging from 26% to 68%.
PD-1 blocking antibodies extend survival among patients with advanced NSCLC; however, these agents have not been evaluated for patients with resectable disease, a group for whom few treatment advances have been made for the past decade.
“Tumor-specific T cells are sitting in the tumor, but they are restrained from being to act by the engagement of PD-1 and PD-L1 in the tumor,” Pardoll said during a press conference. “One blocks that pathway with an antibody. That results initially in an increase of activation of these cells within the tumor, but then the notion is that a portion of them hopefully will spill out of the tumor into the blood, circulate through the body and find those residual few [cancer] cells that have gotten out and intercept those cells from returning and creating the relapse that ultimately kills patients who have had their primary tumor resected.”
Pardoll and colleagues enrolled 22 adults with untreated surgically resectable stage I to stage IIIa NSCLC. Approximately two-thirds (62%) had adenocarcinoma.
Twenty-one patients received two doses of neoadjuvant nivolumab (Opdivo, Bristol-Myers Squibb). Twenty patients underwent surgical resection and received standard postoperative treatment. Median time from the second dose of nivolumab to surgery was 18 days.
Safety and feasibility served as primary objectives. Exploratory endpoints included pathologic and immune response in correlation to the total number of mutations in tumors.
“This was quite feasible, and there were no delays in surgery for enrolled patients who received presurgical nivolumab,” Pardoll said.
An analysis of radiographic responses showed two patients (10%) achieved partial response to two doses of nivolumab, and 18 patients (85%) demonstrated stable disease. One patient (5%) exhibited progressive disease.
“Even though the majority of patients radiographically were stable over the 4 weeks between initiation of nivolumab and surgery, the question is: Does radiology tell the story?” Pardoll said. “What is going on in the tumor? We can, of course, answer that because the tumors are resected.”
To researchers’ surprise, a much larger number of tumors showed significant pathologic regressions as defined by replacement of tumor cells by nontumor cells, Pardoll said.
Researchers observed major pathologic responses in nine (45%) resected tumors. Those responses — defined as 10% or fewer viable cancer cells detectable within the resected tumor after neoadjuvant treatment — occurred in both PD-L1-positive and PD-L1-negative tumors.
Three patients had pathologic complete responses in their primary tumors.
Results showed pathologic response correlated significantly with pretreatment tumor somatic mutation burden.
All patients had been followed for more than 1 year after surgery, and several had been followed for more than 2 years. Two patients who underwent resection had died, but only one death was due to recurrent cancer.
“These results are early and preliminary, but certainly very encouraging,” Pardoll said.
Nearly three-quarters (73%) of the study population remained recurrence free at 18 months, and median RFS had not been reached at the time of analysis.
T-cell clones shared between peripheral blood and the tumor increased systemically after anti-PD-1 treatment in eight of nine patients evaluated.
Researchers hypothesized that checkpoint blockade induces the expansion of tumor-specific T cells in the circulation. To test this theory, they assessed T-cell responses in the blood on the day of nivolumab administration, as well as 44 days after surgery.
“There was a big burst of tumor-specific T cells in the blood within, in most cases, 4 weeks after initiation of anti-PD-1 treatment, suggesting that neoadjuvant treatment may have enhanced antitumor immunity systemically,” Pardoll said in the release. “[Although] it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation in a larger study, we are very optimistic that this approach will eventually be practice changing and may augment or even replace chemotherapy prior to surgical resection.
Researcher Patrick Forde, MBBCh, assistant professor of oncology at Bloomberg-Kimmel Institute for Cancer Immunotherapy, expressed enthusiasm for the results but emphasized confirmation in a larger patient population is necessary.
“We have to be careful not to compare these outcomes with historical outcomes given the small size of this single-arm study,” Forde said in the release. “However, these initial results are highly encouraging and, allied to the translational science, will spur interest in further neoadjuvant clinical trials across tumor types.” – by Mark Leiser
Reference:
Forde PM, et al. Abstract CT079. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosure: Pardoll reports consultant roles with Aduro Biotech, Amgen, Bristol-Myers Squibb, DNAtrix, DNAX, Dracen, Five Prime Therapeutics, FixBio, Immunomic, Janssen, MedImmune, Merck, Pfizer, Potenza, Tieza, Tizona and WindMIL; stock ownership in Aduro Biotech, DNAtrix, Dracen, Five Prime Therapeutics, FixBio, Tieza, Tizona and WindMIL; and patents with Aduro Biotech, Bristol-Myers Squibb, Immunomic and WindMIL. Forde reports research funding from AstraZeneca, Bristol-Myers Squibb, Kyowa and Novartis, as well as consultant roles with AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Inivata, Merck and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Alice T. Shaw, MD, PhD
This is a very exciting and interesting study that shows, for the first time, that in lung cancer the benefit of immunotherapies may extend beyond advanced or metastatic disease to early-stage disease. This was a small pilot study, but the findings are very compelling, particularly the pathologic response rate of 45%.
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Edwin Yau, MD, PhD
This study is very provocative. Based on preclinical studies, the rationale makes sense that neoadjuvant immunotherapy probably will be more effective than adjuvant immunotherapy.
These data could be potentially paradigm changing for us. Although we are detecting more early-stage lung cancer due to screening, we still would like to improve survival for these patients. Neoadjuvant therapy typically has been administered in the setting of locally advanced disease, in consultation with multidisciplinary teams, to try to shrink tumors to allow patients to get to resection.
As far as improving outcomes after resection, that is what is provocative about this study. The responses they saw in this small cohort of patients definitely were impressive. They did have several patients with stage II disease, so it is provocative to think that anybody going for lung cancer surgery potentially could benefit from a relatively easily administered regimen, and we’ll be excited to see the long-term follow-up. We’ll have to relate it to whatever data comes out from the Alliance and ALCHEMIST trials with adjuvant immunotherapy, as well as data from the PACIFIC trial showing that this strategy might also work. It’s great to have so many options, but we definitely will be very interested to see how these neoadjuvant studies play out. There also are neoadjuvant chemotherapy-immunotherapy trials, many of which look promising, as well. I think the neoadjuvant story is something to definitely keep an eye on.
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