2015美国癌症研究学会（AACR）相关信息

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Pembrolizumab Nears 50% Response in High PD-L1–Expressing NSCLC

Pembrolizumab (Keytruda) had an overall response rate (ORR) of 45.2% among a cohort of patients with high PD-L1-expressing non–small cell lung cancer (NSCLC) in the phase I KEYNOTE-001 trial. Regardless of PD-L1 expression, the PD-1 inhibitor was shown to be safe and effective, with an ORR of nearly 20% in the overall study population. The results were presented at the 2015 AACR Annual Meeting and simultaneously published online in The New England Journal of Medicine.

“These results have the potential to substantively change the way that lung cancer is treated,” said lead author, Edward Garon, MD. “The effectiveness of pembrolizumab in treating patients with NSCLC and the prolonged duration of their responses is quite exciting,” added Garon, who is medical director of Thoracic Oncology at UCLA’s Jonsson Comprehensive Cancer Center.

The KEYNOTE-001 trial included 495 previously treated and treatment-naïve patients with advanced or metastatic NSCLC. The total population comprised a training set of 182 patients and a validation set of 313 patients. Pembrolizumab was administered at three dosages: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. The researchers assessed patient responses every 9 weeks.

In the entire study population, the ORR was 19.4% and median overall and progression-free survival were 12.0 and 3.7 months, respectively. The median duration of response was 12.4 months.

“The median duration of response exceeded a year among responders regardless of the degree of PD-L1 expression, which is one of the exciting outcomes with this class of drug,” said Garon.

In the validation group, researchers were able to evaluate PD-L1 expression in 204 patients using an IHC clinical trial assay (CTA). Patients were divided into three groups, based on whether they had membranous PD-L1 expression in their tumor cells of ≥50% (n = 73), 1%-49% (n = 103), or <1% (n = 28).

ORR in the three groups was 45.2%, 16.5%, and 10.7%, respectively. The results were comparable but slightly better among patients who had not received prior therapy versus those who were previously treated.

Survival data were also presented at AACR for 356 patients in the total population whose PD-L1 levels were evaluable by the CTA. After a median follow-up of 10.9 months, OS was not yet reached in the high PD-L1 group (n = 119) and was 8.8 months in both the intermediate (n = 161) and low (n = 76) PD-L1 groups. PFS was 6.3, 3.3, and 2.3 months in the three groups, respectively. The duration of response was similar in the three cohorts at 12.4 months, 10.3 months, and not yet reached.

“In addition to being the largest data set of lung cancer patients treated with this type of drug, this is the first independent validation that PD-L1 expression in tumors is clearly a marker of response,” said Garon.

Overall, pembrolizumab was considered tolerable. Grade ≥3 adverse events occurred in 9% of patients. Immune-related adverse events reported in ≥2% of the population included pneumonitis, hypothyroidism, and infusion reactions. Pneumonitis was the cause of the one treatment-related death in the study.

Pembrolizumab, which is already approved for patients with advanced melanoma, received an FDA breakthrough therapy designation in October 2014 for patients with EGFR-negative and ALK-rearrangement–negative NSCLC whose disease has progressed on or following platinum-based chemotherapy.

Merck, which manufactures pembrolizumab, is hoping that the drug will become the second PD-1 inhibitor approved in lung cancer. In March, the FDA approved nivolumab (Opdivo) for the treatment of patients with advanced squamous NSCLC who have progressed on or after platinum-based chemotherapy.

For his part, Garon seemed to indicate he would welcome pembrolizumab as an addition to the lung cancer armamentarium. “Neither the drug nor the biomarker test [used in KEYNOTE-001] is approved for use in this setting at this time, but if I had a patient whose tumor had PD-L1 expression on at least half of the cells and if pembrolizumab was available, I think that I would find the data compelling to look at the drug as the treatment option for that patient.”

Immune Cell Cancer Immunotherapy Passes First Safety Test in Solid Tumors

Treatment with the cancer immunotherapy known as chimeric antigen receptor T cells, or CAR-T, was found to be relatively safe and feasible in an early-stage study involving a small number of patients with advanced solid tumors, researchers said Sunday.

The data are preliminary but significant as an indication that CAR-T therapies might have a role as a treatment in the much larger solid tumor cancer market. To date, all of the excitement surrounding CAR-T has come from very high remission rates in patients with advanced blood cancers, a smaller commercial market.

The phase I study was conducted using a CAR-T therapy from Novartis (NVS - Get Report) and the University of Pennsylvania. T cells were taken out of patients and modified with receptors to identify a protein known as mesothelin expressed on the surface of certain tumors. The modified T cells, now able to detect and kill mesothelin-containing tumors, were then grown and reinfused back into the patients.

The new immunotherapy, known as CART-meso (short for mesothelin), was administered to five patients with advanced cancers no longer responding to multiple lines of prior therapy. Two patients had ovarian cancer, two had epithelial mesothelioma (a type of lung cancer) and one patient had pancreatic cancer.

No major adverse events associated with the infusion of CART-meso were reported in the five patients, although other serious side effects, including sepsis, shortness of breath and elevated white-blood-cell counts were reported during follow-up. In addition, the modified T cells were detectable in patients' blood for up to 28 days following infusion, and there was some evidence that the T cells migrated to the tumors, said principal investigator Dr. Janos Tanyi of the University of Pennsylvania.

"The interim results to date indicate that the therapy is safe in the patients treated so far," Tanyi said, in a statement. Results from the phase I study were disclosed Sunday at the American Association for Cancer Research (AACR) annual meeting.

CART-meso appears well-tolerated so far, but does it work? Anti-tumor efficacy in the study was "suggested" by the clearing of malignant cells in the fluid surrounding the lungs of a single patient, researchers said. There was also imaging and clinical evidence of a tumor stabilizing or shrinking in another patient.

Mesothelin is also found in normal tissue, raising concern that the modified T cells would not only target and kill tumor cells, but also damage healthy tissue and organs. Researcher found some evidence that the CART-meso could be detected in the fluid around the heart of patients, but there were no related toxicities reported.

"We are still evaluating the CART-meso program, so really have no further details to share at this time," said Novartis spokeswoman Dana Cooper, in response to a question about the company's plans to advance CART-meso or any other CAR-T therapies directed at solid tumors.


http://www.thestreet.com/story/1 ... n-solid-tumors.html

Driver of non-small cell lung cancer, FGFR1, also present in 23 percent of small cell lung cancer

Significant new treatments are available or in clinical trials for non-small cell lung cancer. The same explosion in treatment options is not true for the disease’s cousin, small cell lung cancer, the less common and more aggressive form of the disease. Results presented by the University of Colorado Cancer Center at the American Association for Cancer Research Annual Meeting 2015 show the presence of a known driver of non-small cell lung cancer in small cell lung cancer, implying that promising treatments in development for the first may be applicable to the second form of the disease as well.

“There is an unmet need in small cell lung cancer. There have been no significant new therapies developed in 20 years,” says Fred R. Hirsch, MD, PhD, associate director for international programs at the University of Colorado Cancer Center and CEO of the International Association for the Study of Lung Cancer.

One promising new strategy in the treatment of non-small cell lung cancer is the inhibition fibroblast growth factor receptor (FGFR), which helps to signal uncontrolled, cancerous growth in about 21 percent of non-small cell lung cancers. Results presented by Hirsch and colleagues at AACR 2015 show positivity for FGFR1 amplification, mRNA and/or protein expression in 17 of 75 patient samples (22.7 percent) of small cell lung cancer tumors.

“The presence of FGFR1 as a driver mutation in small cell lung cancer implies that we could repurpose drugs that target this amplification in non-small cell lung cancer for the small cell form of the disease,” Hirsch says.

Small cell lung cancer accounts for 10 to 15 percent of all lung cancers, with 5-year survival rates less than half that of non-small cell lung cancer. Because small cell lung cancer shows symptoms much later than non-small cell lung cancer, it is usually diagnosed much later in the course of the disease, commonly after it has metastasized to other parts of the body, and thus many patients die within weeks or months of diagnosis.

The study identifies a subset of patients with small cell lung cancer with potentially over activated FGFR1 pathways as evidenced by FGFR1 gene amplification, increased FGFR1 mRNA levels, and high protein expression.

“This clearly demonstrates that FGFR1 is important in a subgroup of small cell lung cancers. I would say this will lead to a clinical trial of drugs targeting FGFR in small cell lung cancer,” Hirsch says. “The progress of existing drugs targeting FGFR1 means that we could be much closer to offering treatment options to people with small cell lung cancer than if we had been forced to start with a new compound.”

http://www.coloradocancerblogs.org/driver-of-non-small-cell-lung-cancer-fgfr1-also-present-in-23-percent-of-small-cell-lung-cancer/

CT138: Translating preclinical observations to the clinic: Combination of the dual m-TORC1/2 inhibitor AZD2014 and paclitaxel in ovarian and lung cancer.

Background: We have previously immunomagnetically separated cancer cells from ascites samples of patients with ovarian cancer who went on to receive chemotherapy. We reported that a raised p-S6K in cancer cells was associated with chemoresistance (Carden C, et al, Mol Cancer Ther 2012;11:1609-17). We hypothesized that combining chemotherapy with a novel dual m-TORC1/2 inhibitor would be effective in this setting.

Methods: We studied apoptosis induced by paclitaxel (P), AZD2014 (A) and the combination (C) on 2 ovarian (A2780Cis, SKOV3), 2 lung (PC9, H520), 2 breast (MCF7, SKBR3) and 1 endothelial cell line (HUVEC) by quantifying cleaved-PARP using ELISA. We further investigated the effects of each drug and the combination on tumor growth and signal transduction (pSer473-AKT, p-S6) with a combination of P (20 mg/kg/week) and A (50 mg/kg/3 days/week) in 2 xenograft models (A2780Cis and H520). We also designed an investigator-initiated clinical trial of the combination of P 80 mg/m2/week in combination with an escalating dose of A administered twice a day in 2 schedules (2/7 and 3/7 started concomitantly with the P infusions). Radiological response was measured by RECIST and clinical benefit (CB) defined as progression at 14 weeks or later.

Results: There was a major increase in apoptosis induction, as determined by c-PARP levels quantitation, in 3/6 cancer cell lines and the endothelial cell line HUVEC when A was added to P when compared to P alone utilizing concentrations of both drugs at GI50 and 5 x GI50 for 24 hrs. Additive growth inhibition was observed in both xenograft models after 2 weeks of combination treatment with tumor volume increased by 281 ± 98% with the combination (p<0.05), 557 ± 22% in vehicle-controls (V), 420 ± 156% with A alone and 726 ± 182% with P alone in A2780Cis xenografts; and by 196 ± 44% with the combination (p<0.02), 382 ± 51% with V, 276 ± 52% with A and 509 ± 116% with P in the H520 xenografts. There was a reduction in pSer473-AKT and p-S6 levels in xenografts treated in the A and C arms in both models. The recommended phase II dose of the clinical trial is 80 mg/m2/week of P and 50 mg bd 3/7 of A. Within the clinical trial 7 patients with heavily pre-treated ovarian cancer have had 3 partial responses (PR) with 4 of 6 having CB. Furthermore, in a subset of patients with squamous NSCLC pre-treated with docetaxel, 2 of 5 PRs with significant intra-tumoral cavitation were reported, with 3/3 having CB. The clinical trial is currently expanding in ovarian cancer and squamous NSCLC cohorts.

Conclusions: The combination of P+A is effective in preclinical ovarian and lung cancer models, with additive growth inhibition and apoptosis seen. Promising drug combination antitumor activity has also been reported in heavily pre-treated patients with ovarian cancer and squamous NSCLC in an ongoing clinical trial.

Abstract Number:         3595
Presentation Title:        In vivo acquired resistance to the mutant EGFR inhibitor Rociletinib (CO-1686) is associated with activation of the c-MET pathway

Rociletinib is a novel, oral, targeted irreversible inhibitor of the cancer-causing mutant forms of EGFR currently being studied for the treatment of NSCLC. Rociletinib was designed to spare wild-type EGFR signaling. Heavily-pretreated T790M+ patients treated with rociletinib at 500 or 625mg BID demonstrated a 67% objective response rate (n=56, Soria et al., ENA 2014). Despite these promising data, acquired resistance to rociletinib monotherapy is anticipated. To assess the in vivo mechanisms of acquired resistance to rociletinib, mice bearing PC-9 (EGFR del19) human NSCLC tumors were chronically dosed with erlotinib (50 mg/kg QD) or rociletinib (150 mg/kg BID). Rociletinib treated mice had an increased time to tumor progression as compared to erlotinib treated mice. Resistance, as defined by tumors reaching >300mm3, was observed in all (n=10) erlotinib treated mice between days 42-61. Alternatively, resistance to rociletinib was only observed in 3/10 mice after 126 days of dosing. Emergence of the EGFR T790M resistance mutation was detected in all tumors resistant to erlotinib. Erlotinib resistant tumors (n=7) were crossed over to rociletinib monotherapy on day 60 of the study at a mean tumor volume of 500mm3. Rociletinib treatment generated durable tumor regressions in both crossover and monotherapy treated mice, however continued dosing of rociletinib ultimately allowed for the collection of four resistant tumors. Rociletinib resistant tumors were analyzed using the SuraSeq 500 NGS panel, and all harbored copy number gains (n=12-15) in MET and corresponding MET pathway activation as shown by RTK arrays and Western blotting. Combining rociletinib with the MET inhibitor crizotinib caused regression of the MET amplified rociletinib-resistant tumors. In separate experiments, the addition of 50 ng/ml exogenous HGF was sufficient to render several mutant EGFR cell lines immediately resistant to rociletinib, and this effect could be overcome with the combination of rociletinib and crizotinib. Finally, the combination of rociletinib and crizotinib also demonstrated potent activity in a patient derived L858R EGFR xenograft model with MET amplification (14 copies). Taken together, these data show that (1) in a PC-9 “front-line” model of mutant EGFR lung cancer, rociletinib has a longer time-to-resistance than erlotinib; and (2) MET/HGF pathway activation is a likely driver of acquired resistance to rociletinib in patients with mutant EGFR lung cancer, and can potentially be successfully prevented and/or treated with a combination of rociletinib plus a MET tyrosine kinase inhibitor.