Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall ...survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.
Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m
once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.
After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.
At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC).
We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC ...patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.
In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.
CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.
Nivolumab, a monoclonal antibody targeting PD-1, is currently approved for metastatic non-small cell lung cancer (mNSCLC) treatment after failure of first-line chemotherapy. However, only a quarter ...of patients benefit from this therapy with objective clinical response. In this context, there is an unmet need for improved understanding of resistance mechanisms. Thus, we studied a prospective cohort of mNSCLC (n = 61) treated in second or third-line with nivolumab. We analyzed various blood myeloid and lymphoid markers by flow cytometry (176 variables) at baseline, and after 15 and 30 days of therapy. By attempting to link the evolution of peripheral lymphoid, myeloid cells and anti-PD-1 response, we observed that accumulation of lymphoid cells and monocytic MDSC (mMDSC) expressing, respectively, Tim-3 and galectin-9 is implicated in resistance to PD-1 blockade both for patients with primary or acquired secondary resistance to anti-PD-1. In vitro, anti-Tim-3 blocking antibody reverses resistance to anti-PD-1 in PBMC from lung cancer patients and high levels of blood mMDSC negatively impact on anti-PD-1 efficacy. Together, these data underline that the galectin-9/Tim-3 pathway and mMDSC are key mechanisms of primary or secondary resistance to anti-PD-1 and could be a new target for immunotherapy drug combinations.
Purpose: T-cell infiltration is associated with good tumor prognosis in many cancers. To assess the capacity of neoadjuvant chemotherapy
to affect T-cell infiltration in breast cancer, we evaluated ...CD3 and CD8 infiltrates, and the Foxp3 immunosuppressive T cells.
Experimental Design: CD3 + , CD8 + , and Foxp3 + cell infiltrates were detected by immunohistochemistry in a series of 56 breast cancer patients before and after the end
of neoadjuvant chemotherapy.
Results: Poor prognostic factors (negative hormonal receptors, high tumor grade, and nodal involvement) were associated with a significantly
higher number of CD3, CD8, and Foxp3 infiltrates before the beginning of chemotherapy. Chemotherapy resulted in a decrease
in Foxp3 infiltrates, whereas the level of CD8 and CD3 infiltrates remained unchanged. Pathologic complete responses (pCR)
had a drastic decrease of Foxp3 + cells, whereas these cells remained elevated in nonresponders. A cutoff criterion that combined high CD8 infiltration and
no Foxp3 cell infiltration on surgical specimens is associated with pCR with a sensitivity of 75% and a specificity of 93%.
The infiltrate of cytotoxic TiA1 and granzyme B–positive cells was dramatically enhanced after chemotherapy only in patients
with pCR. By multivariate analysis, association of a high CD8 infiltration and no Foxp3 infiltration on final histologic specimens
were independently associated with pCR.
Conclusion: These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence
of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells. These results argue
for the induction of an antitumor immune response by chemotherapy.
Summary Background An effective and well tolerated treatment is needed for patients with early HER2-positive breast cancer who do not achieve a pathological complete response after neoadjuvant ...therapy. The AVATAXHER trial aimed to predict pathological complete response early with the use of PET and to investigate whether the addition of bevacizumab could improve the proportion of patients achieving a pathological complete response in patients unlikely to respond to treatment. Methods AVATAXHER was a randomised, open-label, non-comparative, multicentre phase 2 study that enrolled women (≥18 years of age) with early-stage HER2-positive breast cancer from 26 oncology centres in France. Patients initially received two cycles of neoadjuvant docetaxel (100 mg/m2 intravenously every 3 weeks) plus trastuzumab (8 mg/kg intravenously every 3 weeks then 6 mg/kg intravenously every 3 weeks for the second course). Before the first and second cycles, 18 F-fluorodeoxyglucose (FDG) PET was done and the change in standardised uptake value was used to predict pathological complete response in each patient. Patients who were predicted to be responders on PET continued to receive standard therapy. Predicted non-responders were randomly assigned (2:1) to receive four cycles of docetaxel (100 mg/m2 intravenously every 3 weeks) and trastuzumab (6 mg/kg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks; group A) or continue on docetaxel plus trastuzumab alone (group B). Randomisation was open label and was done by an adaptive minimisation method. Although investigators and patients were aware of group assignment, the anatomo-pathologist in charge of centralised review of surgical samples and lymph nodes was masked to treatment assignment. The primary endpoint was centrally assessed pathological complete response according to the Chevallier classification. Efficacy analyses were done in the intention-to-treat population. Safety analyses in this Article were done on all patients who received at least one dose of treatment starting from cycle 3. Survival outcomes are not yet mature. This study is registered with ClinicalTrials.gov ( NCT01142778 ) and EUDRACT (2009-013410-26). Findings Between May 19, 2010, and Oct 1, 2012, 152 patients were recruited for the study. Ten patients were subsequently excluded, leaving 142 patients in the intention-to-treat population. Of these 142 patients, 69 were predicted by 18 F-FDG PET to be treatment responders after two cycles of treatment. The 73 predicted non-responders were randomly assigned to group A (n=48) and group B (n=25). Pathological complete responses were noted in 37 (53·6%, 95% CI 41·2–65·7) of the PET responders, 21 (43·8%, 29·5–58·8) of those in group A, and six (24·0%, 9·4–45·1) of those in group B. Incidences of grade 3–4 adverse events were similar in all three groups. The most common grade 3–4 adverse events were neutropenia (four in PET responders, five in group A, and three in group B), febrile neutropenia (one, three, and one, respectively), and myalgia (four, none, and one, respectively). Overall, 24 serious adverse events were reported in 15 patients (PET responders: nine events in four 6% of 67 patients; group A: 14 events in ten 21% of 47 patients; group B: one event in one 4% of 25 patients). No deaths occurred during the study. Interpretation In patients with HER2-positive breast cancer, early PET assessment can help to identify non-responders to neoadjuvant docetaxel plus trastuzumab therapy. In these patients, the addition of bevacizumab can increase the proportion of patients achieving a pathological complete response. This potential new role for PET and the activity of bevacizumab in this setting need to be confirmed in larger phase 3 trials. Funding Roche France.
A decrease in thermogenesis is suspected to be implicated in the energy expenditure reduction during breast cancer treatment. This study aimed to investigate the impact of chemotherapy on the ...metabolic activity of brown adipose tissue (BAT) and the link with weight variation.
This was an ancillary analysis of a multicentre trial involving 109 HER2+ breast cancer patients treated with neoadjuvant chemotherapy. A centralised review of
F-FDG uptake intensity (SUV
) in specific BAT regions (cervical and supraclavicular) was conducted on two PET-CT scans for each patient (before and after the first course of chemotherapy).
Overall, after one course of chemotherapy a significant decrease of 4.4% in
F-FDG-uptake intensity was observed. It was not correlated to initial BMI, age or season. During chemotherapy, 10.1% (n = 11) of the patients lost weight (- 7.7 kg ± 3.8 kg; ie, - 9.4% ± 3.7%) and 29.4% (n = 32) gained weight (+ 5.1 kg ± 1.7 kg; ie, + 8.5% ± 2.6%). Among these subgroups, only the patients who had gained weight underwent a significant decrease (13.42%) in
F-FDG uptake intensity (p = 0.042).
This study is the first to highlight in a large cohort of patients the negative impact of chemotherapy on brown adipose tissue activity. Weight gain during chemotherapy could thus potentially be explained in part by a decrease in brown adipose tissue activity.
To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable.
Three thousand ten ...patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS).
Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively.
After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.
This article describes the Personalized Reimbursement Model (PRM) program methodology, limitations, achievement and perspectives in using real-world data of cancer drugs use to improve and ...personalize drug pricing and reimbursement in France.
PRM platform aggregates Electronic Pharmacy Records (EPR) data from French medical centers (PRM centers) to build retrospective cohorts of patients treated with injectable cancer drugs in a hospital setting. Data extracted on January 1st, 2020, from breast cancer (BC) patients who received trastuzumab, trastuzumab emtansin or pertuzumab since January 1st, 2011, and from lung cancer (LC) patients who received bevacizumab or atezolizumab since January 1st, 2015, enabled recovering their injectable cancer drugs history from diagnosis date until December 30th, 2019, and served as dataset for assessment.
123 PRM centers provided data from 30,730 patients (25,660 BC and 5,070 LC patients respectively). Overall, 20,942 (82%) of BC and 4,716 (93%) of LC patients were analyzed. Completion rate was above 98% for patients characteristics, diagnostic and treatment related data. PRM centers cover 48% and 33% of BC and LC patients in-hospital therapeutic management in France, respectively. Distribution of BC and LC patients therapeutic management, by medical center category and geographic location, was similar in PRM centers to all French medical centers, ensuring the representativeness of the PRM platform.
PRM Platform enabled building a national database generating on demand Real-World Evidence based on EPR. This enabled the first performance-based risk-sharing arrangements based on PRM data, between the CEPS and Roche, for atezolizumab cancer immunotherapy in metastatic non-small cell lung cancer indication.
The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I<O before chemotherapy independently predicted overall survival. This ...study investigates the relevance of I<O measured during chemotherapy for survival and symptoms. The circadian rest‐activity pattern was monitored for 3 days using a wristwatch actigraph while 77 patients were receiving a chemotherapy course within an international randomized Phase III trial. Treatment consisted of first‐line chronomodulated or conventional delivery of 5‐fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer. I<O was computed as the percentage of minutes of activity counts in bed which were below the median of activity out of bed. Circadian disruption was defined by I<O equal to or less than 97.5%. Circadian disruption occurred in 39 patients (51%) on chemotherapy. It was associated with a significantly shorter overall survival, independently of other prognostic factors (multivariate Hazard Ratio: 2.12; p = 0.004). The median survival of patients with a robust circadian rhythm was 22.3 months as compared to 14.7 months in those with circadian disruption during chemotherapy. No toxicity was significantly associated with circadian disruption, but the incidence of grade ≥2 fatigue and of body weight loss ≥5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy‐induced circadian disruption might reduce toxicity and improve efficacy in cancer patients.
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