The benefits of immunotherapy with programmed cell death (PD) inhibitors appear to continue after disease progression in patients with non–small cell lung cancer (NSCLC). Findings from two studies suggest that the effects of the drugs are ongoing if the drugs are continued, and they improve the results of salvage chemotherapy.
Both studies were presented here at the European Lung Cancer Conference (ELCC) 2017.
Better Response to Chemo After Immunotherapy?
The data suggesting that patients have a better response to chemotherapy after they have previously been treated with immunotherapy come from a retrospective analysis of 82 patients with stage IV NSCLC. That study (abstract 91PD)included 67 patients who had previously been treated with various PD inhibitors, and 15 who had not been treated with PD inhibitors. The 15 patients who had not been treated served as controls.
For those who had previously been treated with checkpoint inhibitors, partial response rates to salvage chemotherapy were significantly higher, and the patients were less likely to experience disease progression.
The immune checkpoint inhibitors were nivolumab (Opdivo, Bristol-Myers Squibb Company), used in the previous treatment of 56 (84%) patients; pembrolizumab (Keytruda, Merck), used in seven (10%) patients; and atezolizumab (Tecentriq, Genentech), used in four (6%) patients.
Docetaxel was the most commonly used salvage chemotherapy. It was used in a little more than half (55%) of the case patients and in nearly all (93%) of the control patients. Pemetrexed and paclitaxel were the other agents used.
A partial response to chemotherapy was seen in 18 (27%) case patients and only one (7%) control patient (odds ratio, 0.30; P < .001); 15 (22%) case patients and six (40%) control patients experienced disease progression. Stable disease was documented in 34 (51%) case patients and eight (53%) control patients.
Lead researcher Sacha Rothschild, MD, PhD, Division of Oncology, Department of Medicine, University Hospital Basel, Switzerland, said: "At this point, we can only speculate on the reasons for better response in those pre-treated with checkpoint inhibitors.
"Probably, the activation of the immune system by checkpoint inhibition might render tumor cells more sensitive to chemotherapy. Or chemotherapy may help the tumor-specific T-cells to enter the tumor microenvironment and to exert their function."
Commenting on the study, Marina Garassino, MD, head of thoracic medical oncology at the National Cancer Institute of Milan, Italy, noted, "This is the first research suggesting that chemotherapy could potentially work better after immunotherapy.
"All of us treating patients with immunotherapy have had a feeling about this because we've seen unexpected results with some patients, but this is the first study in which this phenomenon is formally described."
This is the first study in which this phenomenon is formally described. Dr Marina Garassino
Despite the preliminary nature of the findings, Dr Garassino believes that the results "suggest that immunotherapy can change the natural history of the disease and the microenvironment of the tumor, therefore rendering it more sensitive to chemotherapy" and potentially opening up novel avenues of research and treatment.
Discussing the findings, Simon Ekman, MD, PhD, Department of Oncology, Karolinska University Hospital, Stockholm, Sweden, said that the question now is, "How do we combine immunotherapy with chemotherapy? Should we use immune therapy first, like in this trial or...should we combine concomitantly?"
Offering evidence for each scenario, he said the question is how "we awaken the force of the immune system," adding: "It's really about triggering the immune system in different parts of the cancer-immunity cycle and, in the end, causing as much killing of cancer cells as possible."
Dr Ekman believes that on the basis of the evidence so far, "there are several ways of doing it." Listing some potential do's, don'ts, and 'maybes,' he said: "What seems reasonable is to combine the immunotherapy with chemotherapy or antiangiogenic agents.
"Maybe a 'don't' is to not use immunotherapy in EGFR mutation patients. We also have some inconclusive data ― a maybe ― and that is immune therapy in never-smokers and in patients with CNS metastases," he added.
The other study was a post hoc analysis of a phase 2 trial (abstract 96PD) that showed
that continuing PD-L1 inhibitor therapy with atezolizumab after disease progression led to tumor stabilization or tumor shrinkage in 82% of NSCLC patients and an increase in overall survival.
Angel Artal-Cortes, MD, medical oncologist, University Hospital Miguel Servet, Zaragoza, Spain, who led the study, said: "We found that there was a benefit for some patients continuing with the drug, even after a CT scan suggested progressive disease.
"Atezolizumab can control lung cancer for a longer period of time than was initially thought," Dr Anal-Cortes commented in a conference press release.
Another finding was that using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) criteria to assess disease progression may underestimate the effect of immunotherapies in comparison with immune-modified RECIST (imRECIST), with lower disease control rates and progression-free survival.
Dr Artal-Cortes believes that imRECIST "should be kept in mind" when deciding whether or not to continue atezolizumab therapy in patients responding to drug therapy who have a good performance status and have no serious toxicities.
Commenting on this study, Dr Garassino went further, saying that compared with imRECIST, "conventional RECIST may not be the best criteria to evaluate response to immunotherapy."
She noted that although these findings need to be confirmed in further studies, "The research suggests that immunotherapy can be prolonged when the new criteria are used," even if there is progression as determined on the basis of the RECIST v1.1 criteria.
The second study was a retrospective analysis, which indicated that patients with stage IV NSCLC who had previously been treated with checkpoint inhibitors and who had significantly higher partial response rates to salvage chemotherapy than other patients and were less likely to experience disease progression.
Dr Garassino welcomed the study, commenting: "This is the first research suggesting that chemotherapy could potentially work better after immunotherapy."
She believes that although the findings are preliminary, "they suggest that immunotherapy can change the natural history of the disease and the microenvironment of the tumor, therefore rendering it more sensitive to chemotherapy" and potentially opening up novel avenues of research and treatment.
The data for this study come from the phase 2 POPLAR study, a randomized trial that compared atezolizumab with docetaxel in patients with previously treated advanced or metastatic NSCLC.
The analysis was restricted to patients with lung tumors that showed high PD-L1 expression. The team studied 387 patients who were randomly allocated to receive atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or docetaxel 75 mg/m2 every 3 weeks until disease progression, determined on the basis of RECIST v1.1 criteria.
Evaluating the 114 patients who received atezolizumab, using imRECIST and postprogressive disease radiographic changes, the team found that the overall response rate was 15% on RECIST v1.1 vs 17% with imRECIST.
Furthermore, the disease control rate, comprising complete responses, partial responses, and rates of patients with stable disease, was 52% on RECIST v1.1 vs 65% with imRECIST. Median progression-free survival was 2.7 months and 4.3 months, respectively.
Sixty-one atezolizumab patients continued with the treatment following initial disease progression, as defined using RECIST v1.1. The median treatment duration was 1.8 months, with 62% treated for less than 3 months.
The researchers calculate that, relative to the time of disease progression, 8% of patients who continued with atezolizumab had a subsequent 30% decrease in target lesions, whereas 74% had a best change of between +20% and -30%.
Median overall survival was 11.8 months in these patients, compared with 9.2 months among atezolizumab patients who received other anticancer treatments post disease progression and 1.8 months in those who received no further anticancer treatment.
The median overall survival among docetaxel patients who received nonprotocol anticancer therapy following disease progression was 9.7 months, compared with 3.8 months among those who did not have further therapy.
Exactly what lessons to draw from these observations remians unclear, suggested
study discussant Rolf A. Stahel, MD, Department of Hematology and Oncology, Clinic of Oncology, University Hospital Zurich, Switzerland. "What could we conclude in this difficult area?" he asked the audience, reminding them, "Our knowledge on the evolution of the clinical course post progression from immune checkpoint inhibitors is really at its infancy."
Noting the treatment response in 8% of patients who continued with immunotherapy beyond disease regression, he said: "I think it's important for all those industry-sponsored trials, as well as the academically sponsored trials, that we continue to document what happens to our patients on immune therapy beyond the primary endpoint, to learn more."
Dr Stahel added that, to know the right direction for future therapy, he feels that what is needed are studies comparing, for example, the addition of chemotherapy or another immune checkpoint inhibitor vs a switch to chemotherapy.
"And this can only be done in randomized trials," he emphasized.
No funding has been declared for the chemotherapy after immunotherapy study, and the investigators have disclosed no relevant financial relationships. The atezolizumab continuation study was funded by F. Hoffmann-La Roche Ltd/Genentech Inc. Dr Artal-Cortes sits on advisory boards for Roche, BMS, and MSD and has received travel fees from Roche. Other authors have also disclosed relationships with industry.
European Lung Cancer Conference (ELCC) 2017. Abstract 96PD_PR, presented May 6, 2017; abstract 91PD_PR, presented May 7, 2017.