2015年第16届世界肺癌大会（WCLC)

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1. Atezolizumab Plus Chemo Leads to High Response Rate in NSCLC

Patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) had double the expected response when the PD-L1 inhibitor atezolizumab was added to chemotherapy, according to preliminary data from an ongoing clinical trial reported at the 2015 World Conference on Lung Cancer. Overall, almost two thirds of 41 evaluable patients had objective responses with atezolizumab plus different platinum-based chemotherapy doublets. The highest response rate occurred with the combination of atezolizumab, carboplatin, and pemetrexed, as 13 of 17 patients (76.5%) had partial responses. Four patients treated with the anti–PD-L1 inhibitor, carboplatin, and nab-paclitaxel had complete responses. “This preliminary analysis showed a high response rate for the combined non–small cell lung cancer cohort, supporting potential synergy between atezolizumab and chemotherapy,” said D. Ross Camidge, MD, PhD, a professor of medical oncology at the University of Colorado in Denver. “Atezolizumab demonstrated no unexpected toxicities in combination with standard first-line chemotherapy regimens for advanced non-small cell lung cancer.” Despite advances in treatment of NSCLC, the overall response rate with first-line standard chemotherapy for metastatic disease remains about 30%. Preclinical studies have suggested that chemotherapy leads to antigen release in the tumor microenvironment, potentially affording an opportunity for enhanced effects of immunotherapy. “Combining PD-L1 inhibition with chemotherapy could create an immunogenic ‘feedback loop,’ increasing the number of antigens presented to the T-cells, thus increasing immune responses and changing the tumor microenvironment to be more favorable to immune response,” said Camidge. Atezolizumab (formerly MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint but not PD-L2/B7.1 interaction, thus avoiding the risk of autoimmune lung toxicity. Atezolizumab demonstrated single-agent activity in preliminary clinical studies involving patients with advanced lung cancer, providing a rationale to evaluate the immunotherapeutic agent in combination with standard chemotherapy regimens for advanced NSCLC. Camidge reported findings from a phase Ib trial involving patients with previously untreated metastatic NSCLC. The patients received atezolizumab at a dose of 15 mg/kg IV every 3 weeks in addition to one of three chemotherapy doublets: carboplatin paired with paclitaxel, pemetrexed (nonsquamous histology only), or nab-paclitaxel. Treatment continued for four to six cycles, followed by atezolizumab maintenance therapy until disease progression (and optionally, pemetrexed maintenance in that arm of the trial). The primary outcome was overall response rate, as determined by RECIST criteria. The trial has an accrual goal of 25 patients per treatment group, and Camidge reported data for 58 patients, 41 of whom were evaluable for response. The patients had a median age of 65, and 79% of the cohort had nonsquamous histology. PD-L1 expression was assessed by immunohistochemistry. Response data showed that four of eight (50%) patients in the carboplatin-paclitaxel cohort achieved objective responses (all partial responses), as did nine of 16 (56%) patients who received carboplatin and nab-paclitaxel in addition to atezolizumab (including all complete responses that have occurred thus far). Overall, 26 of the 41 (63.4%) evaluable patients met criteria for objective response, led by a 77% response rate in the pemetrexed arm. “The vast majority of patients in all three groups had regression of tumor burden, even though the change did not meet criteria for objective response in all cases,” said Camidge. All 58 patients were included in the safety analysis. The most common grade 3/4 adverse events across the three treatment groups were neutropenia (36% to 45%, 40% overall); anemia (8.3% to 20.0%, 13.8% overall); and thrombocytopenia (0% to 21%, 12.1% overall). A preliminary analysis of individual types of adverse events suggested that atezolizumab did not add substantially to the adverse events usually observed with cytotoxic chemotherapy. “Analysis of the data by specific chemotherapy regimen, corticosteroid use, and PD-L1 expression levels are in progress,” said Camidge. “Other endpoints, including duration of response and progression-free survival, are still immature and will be presented at a later data. “Several phase III studies looking at atezolizumab monotherapy and in combination with other agents in non-small cell lung care are underway.”

2. Deep Sequencing Reveals Possible Primary Resistance Mechanism in EGFR-Mutant NSCLC

Coexisting driver mutations in EGFR-mutant non–small cell lung cancer (NSCLC) could potentially contribute to primary resistance to EGFR-targeted therapy, according to a presentation during the Presidential Plenary Symposium at the 2015 World Conference on Lung Cancer. "With targeting EGFR, this is something we know works well, and what we're trying to get closer to is defining subsets within that group, so that we can maximize potential responses," Daniel S. W. Tan, MBBS, BSc, MRCP, consultant, Division of Medical Oncology, National Cancer Centre Singapore, and clinician scientist fellow, Genome Institute of Singapore, said during a presentation of the results. “It is likely that additional subgroups within T790M-positive and -negative patients, such as those with high mutation burden, will further emerge, and may form the basis for novel therapeutic approaches, including immunotherapy.” In the study, whole exome and transcriptome sequencing was conducted on tumor samples from patients who were naïve or resistant to EGFR TKIs across two cohorts. In the first group, tissue samples were obtained during surgery for patients with stage I/II resected TKI-naïve NSCLC. In this cohort, the excised tumor was divided into sectors (4-11 sectors per tumor), each of which was examined by next-generation sequencing. In a second cohort, biopsy samples were explored from patients with stage IV EGFR TKI-resistant NSCLC. The overall goal of the study was to determine the clonal architecture of the tumor through multi-sector sequencing. This information could help illuminate possible causes for varying responses to frontline EGFR inhibition. Additionally, for samples from the second cohort, the study hoped to determine potential mechanisms of EGFR TKI resistance. Overall, 8 tumors were available for multi-sector analysis, with each containing an average of 54 coding exome alterations. All samples came from patients without a history of smoking, which may have contributed to an unusually low mutation burden seen in the study, Tan suggested. EGFR mutations were found across all sectors in each tumor, in the "trunk" region, representing a driver mutation. Overall, 5 were L858R mutations (62.5%), 2 were exon 19 deletions (25%), and 1 was an exon 20 insertion (12.5%). Despite utilizing ultra-deep sequencing, T790M mutations were not detected in any sectors in TKI-naïve patients. Although EGFR was present in the trunk of all samples, other alterations were also found to coexist, including TP53 and PTEN. When looking at the two cohorts together, two patients in the TKI-naïve arm had expression profiles that were similar to those in the TKI-resistant arm. In one of these patients with EGFR L858R-mutant stage IB NSCLC, 3 additional driver mutations were identified (CLIP1, PTEN splice site, and MAP3K19). In this example, the patient relapsed within 5 months of surgery. "This particular tumor had co-existing truncal driver mutations, suggesting that multiple driver events could account for the 10% to 20% of patients who don't respond very well," Tan said. "It is very early data that we're generating and we'll hopefully be generating more data in the future." In evaluable samples from the second cohort (n = 24), T790M mutations were the most common resistance mechanism (54%). In T790M-mutant samples, non-overlapping coexisting alterations were seen in MET (8%) and HER2 (4%). In those with T790M-negative tumors, 16% were found to have high mutation burdens, which were associated with a smoking history or APOBEC mutational signatures. In the T790M-negative group, alterations were also seen in MET (13%), HER2 (4%), and HER2 plus MET (4%). "We now have third-generation drugs to tackle T790M, but they don't happen in isolation. In this case, this did coexist with both MET and HER2 amplification," Tan said. "More interestingly, when we looked at the subset of resistant tumors, a small group had a higher mutation burden." Findings from this study could help guide future clinical trials for patients with EGFR TKI-resistant tumors, specifically those with a high tumor burden. Early evidence reported at the 2015 ASCO Annual Meeting suggested that tumors with a higher tumor burden were more susceptible to immune checkpoint inhibition. "With a high mutation burden, we are beginning to get some data with immunotherapy approaches," Tan said. "They may be patients that we could consider for immunotherapy trials." For those with T790M-mutant NSCLC, there are a number of third-generation TKIs in development. In early August, Clovis Oncology completed a new drug application for rociletinib in patients with EGFR T790M-positive metastatic NSCLC, based on phase I/II TIGER-X trial.  Additionally, during the summer, AstraZeneca submitted a new drug application for osimertinib (formally AZD9291), based on two phase II studies, AURA and AURA2. This application has received a priority review designation from the FDA as a treatment for patients with T790M alterations, with a decision expected in early 2016.

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3. Transgene Announces Final Overall Survival Data from Phase 2b TIME Trial with TG4010 Immunotherapy in NSCLC

全文：http://www.transgene.fr/wp-conte ... SLC-revised-BIS.pdf

4. Nivolumab/Ipilimumab Combination Active in Advanced NSCLC

A chemotherapy-free regimen of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated activity as a first-line therapy for patients with advanced non–small cell lung cancer (NSCLC), according to a preliminary clinical trial presented at the 2015 World Conference on Lung Cancer. Four different regimens of the PD-1 inhibitor nivolumab and the anti-CTLA-4 antibody ipilimumab led to response rates of 13% to 39% in 148 patients with no prior exposure to systemic therapy. The combination produced responses that were both deep and durable with a low rate of treatment-emergent grade 3/4 adverse events (AEs) leading to discontinuation. “Clinical activity was observed regardless of tumor PD-L1 expression,” said lead investigator Naiyer A. Rizvi, MD, director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center. “We have preliminary evidence of greater activity in tumors that have 1% or greater PD-L1 expression. The median disease control rate [response plus stable disease] was not reached in any arm, regardless of PD-L1 expression.” The lung cancer clinical development program for nivolumab includes the CheckMate-012 Trial, which is evaluating nivolumab in previously untreated stage IIIB/IV NSCLC as monotherapy and in various combinations with cytotoxic and targeted therapies. Investigators in CheckMate-012 evaluated four administration/dosing schedules for the combination of nivolumab and ipilimumab. In arm A, both agents were administered at a dose of 1 mg/kg every 3 weeks (Q3W, N = 31). In arm B nivolumab was administered at 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg every 6 weeks (Q6W; N = 40). Arm C and D dosed nivolumab at 3 mg/kg Q2W and ipilimumab 1 mg/kg every 12 weeks (Q12W; N=38) or Q6W (N = 39). Across the four groups, the patient cohorts had a median age of 62 to 68, stage IV disease in more than 90% of cases, nonsquamous histology in more than 80%, and ECOG 0-1 performance status. All four regimens demonstrated activity, with the arms containing nivolumab at 3 mg/kg showing the best objective response rate (ORR). In arm C, the ORR was 39% and in arm D the ORR was 31%. The ORRs were 25% and 13%, in arm B and arm A, respectively. Median PFS ranged from 4.9 months in arm B to 10.6 months in arm A. Median PFS was 8 months in arm C and 8.3 months in arm D. The 24-week PFS was 55% in arm A, 63% in arm C, and not yet reached in the other two groups. Median overall survival was not yet reached in all four arms (follow-up range, 6.2-16.6 months). In those with ≥1 PD-L1 expression by IHC (n = 77; 68%) the ORR was 8%, 24%, 48%, and 48% in arms A, B, C, and D, respectively. Median PFS across each arm were 11.5 weeks, 21.1 weeks, 34.6 weeks, and not reached and the 24-week PFS rates were 42%, 40%, 74%, and 65%, respectively. Treatment-emergent grade 3/4 adverse AEs occurred in 28% to 35% of patients in each group but led to discontinuation in just 3% to 10% of cases. All grade treatment-related AEs occurred in 77%, 73%, 74%, and 69% of patients in groups A, B, C, and D, respectively. The safety profile was consistent with previous studies of the combination, and the discontinuation rate associated with AEs was similar to rates observed with nivolumab alone. The only grade 3/4 adverse events that occurred in as many as 10% of patients were hepatic in arm B (10%) and skin-related in arm C and D (13%). Grade 3/4 pulmonary AEs occurred in no more than 3% of patients in any of the groups. There were no treatment-related deaths in the trial. The rationale for evaluating nivolumab and ipilimumab includes the observation that both agents enhance T-cell antitumor activity through different but complementary mechanisms, said Rizvi. Preclinical studies have suggested the combination has synergistic activity as compared with either agent alone, observations that were supported in clinical trials of the combination in advanced melanoma. “Clinical results from Opdivo+Yervoy have already been reported in previously untreated metastatic melanoma, showing the potential of dual immune checkpoint blockade targeting both PD-1 and CTLA-4,” Rizvi said in a statement. “The preliminary results from this trial in advanced non-small cell lung cancer similarly push the envelope of benefit with an immunotherapy combination strategy in the first-line treatment of advanced non-small cell lung cancer which warrants further studies.” An ongoing phase III trial is comparing nivolumab alone or in combination with ipilimumab versus platinum-based chemotherapy in patients with advanced NSCLC and no prior exposure to chemotherapy. In two phase III trials, single-agent nivolumab led to improved overall survival compared with docetaxel in patients with previously treated, advanced NSCLC, regardless of histology. In addition to indications in melanoma, Nivolumab has an FDA approval for the treatment of patients with metastatic squamous-cell NSCLC that progressed on or after treatment with platinum-based chemotherapy. Additionally, an application for the drug in previously-treated patients with metastatic nonsquamous cell NSCLC was granted a priority review by the FDA, with a decision deadline of January 2, 2016.

5. Further evidence for the potential of AZD9291 in NSCLC presented at WCLC

AstraZeneca has announced updated data on AZD9291 in first-line patients with epidermal growth factor receptor mutation (EGFRm) positive advanced non-small cell lung cancer (NSCLC) and previously-treated patients with EGFRm T790M mutation-positive NSCLC.

The data, from the AURA Phase I trial first-line cohort and two AURA Phase II studies, were presented at the World Conference on Lung Cancer (WCLC) 2015.

Data demonstrated that in 60 patients who received AZD9291 once daily in the first-line setting, 72% were progression free (PFS) at 12 months. Confirmed overall response rate (ORR) was 75%. The longest duration of response (DoR) was ongoing at 18 months.

“While the data are still preliminary, these latest results from the AURA trial first-line cohort further reinforce the potential of AZD9291 in treatment-naïve EGFRm advanced NSCLC patients,” said Professor Suresh S. Ramalingam, Chief of Thoracic Oncology and Director of Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.

Data on two AURA Phase II studies (AURA extension and AURA2) in previously treated patients with EGFRm T790M were also presented. While still preliminary, these studies showed an efficacy and tolerability profile for AZD9291 consistent with previously-reported data. In AURA extension, ORR was 61%. Consistent results were observed in AURA2, ORR was 71%; median DoR was 7.8 months and median PFS was 8.6 months.

Data supports AstraZeneca’s accelerated strategy with AZD9291

“These data provide further evidence of the encouraging durable response with AZD9291 in treatment-naïve and pre-treated patients with advanced EGFRm NSCLC”, said Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca. “The data support our accelerated development strategy with AZD9291, which has moved with unprecedented speed from first human studies to the US Food and Drug Administration and other regulatory submissions. With AZD9291 now under review by global regulatory authorities, we are on track to bring this innovative medicine to patients as quickly as possible to address this critical need.”

Marketing authorisation applications for AZD9291 for the treatment of EGFRm T790M mutation-positive NSCLC have been submitted to the US Food and Drug Administration (FDA), the European Medical Agency (EMA) and other regulatory authorities.

6. A Novel Antibody-Drug Conjugate and Chemotherapy’s Future in Lung Cancer

Following the conclusion of the 16th World Conference on Lung Cancer (WCLC), held September 6–9 in Denver, Colorado, we spoke with Dr. David Ross Camidge, director of the thoracic oncology clinical and research programs at the University of Colorado, about the results of an early-phase antibody-drug conjugate lung cancer trial that he presented at the meeting, and the evolving role of chemotherapy in the treatment of advanced lung cancer.

Cancer Network: First, can you tell us about this antibody-drug conjugate trial. What is the target of this antibody and what is the toxin it’s linked to?

Dr. Camidge: This was a relatively early-phase study with a drug that has possibly one of the longest names out there—sacituzumab govitecan—but in order to be practical it’s called IMMU-132, and it’s an antibody-drug conjugate. Now, what that means is that you have an antibody that is acting as a delivery system to FedEx a toxic molecule, often the same kind of toxic molecule that might be used in chemotherapy, and the goal is to try to get it concentrated into the tumor by using the antibody to direct it into the tumor cells.

There are many antibody-drug conjugates. IMMU-132 uses an antibody directed against TROP-2, a surface marker present on many different solid tumors, including esophageal, gastric, colorectal, prostate, and both small-cell and non–small-cell lung cancers. We are using that antibody to direct SN-38, a toxic drug that is the active ingredient of the well-known chemotherapy called irinotecan. The idea of delivering it here is to get a better efficacy/toxicity ratio (ie, to make it more effective because we are delivering it to the tumor and make it safer because we are not delivering to most normal tissues).

Cancer Network: What were the results of this study so far, and what is next for this agent in lung cancer?

Dr. Camidge: So, we presented data on about just over 50 patients with both small-cell and non–small-cell lung cancers at what we thought were the active doses of this drug. And if we take the non–small-cell group together—and the striking thing is that this was a heavily pretreated group of patients, on average they had had at least three prior lines of therapy and some of them had even received up to eight lines of therapy—we got about 30% to 32% of patients with fairly dramatic shrinkage. So we achieved an objective response—this included patients with squamous lung cancer and adenocarcinoma of the lung—and the median progression-free survival was 5.4 months at the dose [the company] plans on taking forward (10 mg/kg). So it seems to be active in a heavily treated population, and the duration of benefit is quite reasonable.

We showed images of one particular patient who happens to be one of my patients. He had four previous chemotherapies, and I have to say that apart from going bald, which is a side effect of the drug—possibly because that marker is also contained in the skin or hair follicles—he is actually tolerating the drug very well, is still working full time, and in every single scan we have done his tumor looks a little bit smaller. He is coming up to a year on therapy now. This is a guy with a KRAS mutation and he is a heavy ex-smoker, so he doesn’t meet any of the usual criteria for people who are responding to some of the targeted therapies.

The small-cell data was a bit more modest. They were getting about a 30% response rate overall. At the recommended dose, they were getting about a 60% response rate, but that is only three out of five patients treated at that dose, so I don’t know if we can place a lot of confidence that that number is going to stay the same. The median progression-free survival in the small-cell cohort at the recommended dose was 4.6 months—so again, OK, but not perhaps as exciting as the non–small-cell data. But this was also a heavily pretreated population (usually 2.5 prior lines of therapy and ranging from 1 to 7).

Cancer Network: In the context of current chemotherapy lung cancer therapies, which have been the mainstay for lung cancer, and the new anti-PD-1 antibodies that are now available for advanced lung cancer patients, what do you see as the current role of chemotherapy?

Dr. Camidge: So, if you like, an antibody-drug conjugate is sort of in the halfway house of an immunotherapy (where you are really using antibodies to try to turn on the patient’s own immune system to reject the cancer) and chemotherapy (where you are just hoping the treatment is more poisonous to the cancer than to the body). These directed antibodies sit in that middle ground.

I think chemotherapy will continue to have a role, and it will continue to have a role for two things. One is we have not yet cured cancer and so you will need many lines of defense, and maybe we move the ordering of the lines of defense but we are still going to need them. And the other thing, which is interesting, is whether some of these—either chemotherapies or antibody-drug conjugates—may kill cells in a manner that makes them more stimulatory for the immune system. So maybe we are going to need these things in concert.

At the WCLC this year we also saw data on a combination of the Roche/Genentech anti-PD-L1 antagonist with some standard first-line chemotherapy, a relatively small study, but they were getting some astonishingly high response rates, in the 60% to 70% range—of course we haven’t seen how long those responses will last yet. It is an area of interest to see if these things are not mutually exclusive, but have a combinatorial role in the future.

关键词：IMMU-132、SN-38、antibody-drug conjugates、TROP-2

ClinicalTrials.gov Identifier: NCT01631552

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