Dave Levitan

Adding the immunotherapy agent durvalumab to chemotherapy improves overall survival in patients with extensive-stage small-cell lung cancer (ES-SCLC), according to the results of the CASPIAN trial. Findings were presented at the 

International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC)

In this phase III trial, investigators assessed the clinical efficacy and safety of durvalumab with or without tremelimumab with etoposide and carboplatin or cisplatin (EP) chemotherapy followed by durvalumab with or without tremelimumab maintenance therapy compared with EP alone as first-line treatment in ES-SCLC.

“The addition of durvalumab to EP as first-line treatment for extensive-stage non-small cell lung cancer significantly improved overall survival (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of etoposide,” noted lead study author Luis Paz-Ares, MD, of the Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc in Madrid.

A total of 537 previously untreated ES-SCLC patients were randomly assigned to receive 1) durvalumab with 4 courses of EP chemotherapy, 2) durvalumab with tremelimumab and EP for 4 cycles, or 3) EP alone for as many as 6 cycles. Data presented at WCLC 2019 compared the durvalamab arm to a control.

Paz-Ares and colleagues found that 53.7% of patients given immunotherapy were alive at 12 months vs 39.8% of those in the control group. At 18 months, these measures were 33.9% vs 24.7%, respectively. Furthermore, patients in the durvalumab group had a median overall survival of 13 months compared with 10.3 months in the EP control group (hazard ratio [HR], 0.73; 95% CI: 0.591–0.909; 

 = .0047). Clinical benefits were also supported by the progression-free survival and objective response rates in these patients.

“Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease,” added Paz-Ares.

Safety in the study aligned with known safety profiles of the agents used. “In terms of safety, we didn’t identify any new safety signals,” said Paz-Ares. “For most of the cases, toxicity profile was similar among the two study arms, [with the] same number of grade 3–4 events [and] serious adverse events in the two treatment arms. The main difference was in the incidence of immune-mediated events, as anticipated.”

Specifically, in the durvalumab plus EP arm (n = 265), the frequency of grade 3–4 adverse events was 61.5% vs 62.4% in the EP arm. Serious adverse events occurred in 30.9% of patients in the durvalumab plus EP arm vs 36.1% in the EP arm (n = 266). Immune-mediated adverse events occurred in 19.6% of those in the durvalumab plus EP arm vs 2.6% of those in the EP arm.

Of note, ES-SCLC typically carries a poor prognosis, with a mean survival time of 10 months following diagnosis. For more than 30 years, the first-line treatment for ES-SCLC entailed EP with few other options.

Although the initial response rates observed in this study were high, they were not durable, with patients typically relapsing at 6 months. As a first-line treatment, immune checkpoint blockade has demonstrated clinical efficacy in ES-SCLC patients.

“Very importantly, the benefit was seen across all groups, including those [patients] with brain metastases,” concluded Paz-Ares. “Combining durvalumab with either cisplatin- or carboplatin-etoposide in ES-SCLC provides an important new treatment option for patients and physicians.”

James L Mulshine, MD, of Rush University in Chicago, who was not involved in the study, told Cancer Network that the new results could be important.

“This is welcome news in a challenging clinical setting, especially since the addition of blocking PD-L1 in this setting is not associated with significantly great side-effect profile,” he said. “This is an important early signal that merits very close follow-up.”

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In this phase III trial, investigators assessed the clinical efficacy and safety of durvalumab with or without tremelimumab with etoposide and carboplatin or cisplatin chemotherapy followed by durvalumab with or without tremelimumab maintenance therapy compared with EP alone as first-line treatment in extensive-stage small-cell lung cancer.

Extending Survival in Extensive-Stage Small-Cell Lung Cancer

Both bevacizumab and pemetrexed were effective as maintenance therapy for advanced nonsquamous non–small-cell lung cancer (NSCLC),  yet yielded higher toxicity, according to a new study 

. The combination of the two agents yielded similar survival outcomes, but researchers do not recommend its use.

“National Comprehensive Cancer Network guidelines recommend pemetrexed, bevacizumab, or a combination of pemetrexed and bevacizumab as maintenance therapy for advanced NSCLC,” wrote study authors led by 

, of the Winship Cancer Institute of Emory University in Atlanta. “Because these three distinct treatment approaches have not been compared directly, and in view of the important potential toxicity and cost considerations, we conducted a definitive phase III trial to determine the optimal maintenance therapy for advanced nonsquamous NSCLC.”

The new ECOG-ACRIN 5508 study enrolled a total of 1,516 patients with advanced nonsquamous NSCLC, of whom 874 patients (57%) were progression-free after four cycles of carboplatin, paclitaxel and bevacizumab. Those patients were then randomized to receive maintenance therapy with either bevacizumab (287 patients), pemetrexed (294 patients), or the combination of both those agents (293 patients). Most of the cohort was white (87%), the groups had a median age between 63 and 65 years, and 11% of the patients never smoked.

After a median follow-up of 50.6 months, the three maintenance therapy arms had similar overall survival (OS) outcomes. The median OS from randomization was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, for a hazard ratio (HR) of 0.86 (95% CI, 0.70–1.07; 

 = 0.12). The combination group had a median OS of 16.4 months, yielding an HR compared to bevacizumab of 0.90 (95% CI, 0.73–1.12; 

In the pemetrexed group the median progression-free survival (PFS) was 5.1 months, compared with 4.2 months with bevacizumab, for an HR of 0.85 (95% CI, 0.69–1.03; 

 = 0.06). The combination group had a median PFS of 7.5 months, which was significantly better than bevacizumab alone, with an HR of 0.67 (95% CI, 0.55–0.82; 

 < 0.001). Objective response rates during the maintenance phase in the bevacizumab, pemetrexed, and combination groups was 12.5%, 18.7%, and 21.2%, respectively.

The combination of bevacizumab and pemetrexed resulted in higher incidence of several adverse events compared with bevacizumab alone. These included anemia (

“Our results provide evidence that the outcomes are comparable between bevacizumab and pemetrexed, a proven agent in the maintenance therapy setting, from a clinical standpoint,” the authors concluded. They noted that the trial was initiated before targeted therapy or immunotherapy had been proven for first-line therapy in advanced NSCLC; to date, there is still limited information on the interactions between pemetrexed and immune checkpoint inhibition.

“It is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC,” the authors wrote. “The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting.”

Heather Wakelee, MD, of Stanford University Medical Center in California, told 

 agreed the trial was very important when it was designed a decade ago, but there have been significant changes in this disease setting since then.

“We do not use switch maintenance any longer and so these results become less relevant,” she said. “This will not likely change practice.”

A phase III trial found bevacizumab and pemetrexed were effective as a maintenance therapy, but researchers do not recommend it to treat non–small-cell lung cancer.

What Is the Optimal Maintenance Therapy in Advanced NSCLC?

Lurbinectedin showed promising activity as a second-line therapy for small-cell lung cancer (SCLC), according to a phase II trial presented at the American Society of Clinical Oncology (ASCO) Annual Meeting (

). With activity in both chemo-sensitive and -resistant disease and a manageable safety profile, the agent may represent a new treatment option in this setting.

“SCLC is a very aggressive disease with a dismal prognosis with currently available treatments,” said Luis G. Paz-Ares, MD, PhD, of the Hospital Universitario 12 de Octubre in Madrid. He added that topotecan is the only treatment approved by the US Food and Drug Administration over the last 20 years in the second-line setting.

Lurbinectedin is a potent inhibitor of oncogenic transcription, and it demonstrated antitumor activity in a phase I/II study in combination with doxorubicin. Paz-Ares presented results of the new phase II trial of single-agent lurbinectedin in patients with SCLC who had received one prior line of chemotherapy (prior immunotherapy was allowed).

The study included a total of 105 patients, with a median age of 60 years. Most patients were men (60%), and 7.6% of the cohort had received prior immunotherapy. The median chemotherapy-free interval was 3.5 months, and 20% had received chemotherapy less than 30 days prior to initiating lurbinectedin treatment.

The objective response rate was 35.2%; all responses were partial responses, and another 33.3% of the cohort had stable disease. This resulted in a disease control rate of 68.6%. The median duration of response was 5.3 months. Sixty-five percent of patients saw some decrease in tumor size with lurbinectedin.

Among the 45 patients with resistant disease (defined as a chemotherapy-free interval under 90 days), the response rate was 22.2%. Among the 60 sensitive patients, the rate was 45.0%. The median duration of response in the resistant and sensitive patients was 4.7 months and 6.2 months, respectively.

The median progression-free survival (PFS) was 3.9 months, and the 6-month PFS rate was 33.6%. In resistant patients, the 6-month PFS rate was 18.8%, compared with 44.6% in sensitive patients. The median overall survival (OS) was 9.3 months, with a 12-month OS rate of 34.2%. In resistant and sensitive patients, the 12-month OS rates were 15.9% and 48.3%, respectively.

Most patients experienced an adverse event (AE) of any grade (84.8%), and 34.3% of the cohort had at least one grade 3 or higher AE; serious AEs occurred in 10.5% of the cohort. There were no related AEs leading to death, and only 2 patients had a related AE leading to treatment discontinuation; 22.1% of patients required a dose delay, and 26.3% required a dose reduction. Neutropenia was the most common grade 3/4 AE (22.9%), followed by anemia (6.7%), fatigue (6.7%), thrombocytopenia (4.8%), and febrile neutropenia (4.8%).

“Lurbinectedin is emerging as a potential new treatment alternative for the second-line setting in SCLC patients,” Paz-Ares concluded.

 of Massachusetts General Hospital in Boston, was the discussant for the abstract. She said that the response rate in the trial “does stand out” as a numerically higher value than seen in other SCLC studies. “The OS data are somewhat immature, as a third of patients are still in follow-up,” she noted. “And there are shifting standards for first-line therapy, now with more patients receiving combination chemotherapy and immunotherapy.”

Farago said phase III data on lurbinectedin are still needed to move forward, though no randomized single-agent lurbinectedin studies are planned. One large randomized phase III trial is ongoing that compares lurbinectedin in combination with doxorubicin to either topotecan or cyclophosphamide/doxorubicin/vincristine. “We look forward to seeing those results,” she said.

Lurbinectedin may represent a new treatment option as second-line therapy for patients with small-cell lung cancer.

Lurbinectedin Shows Promise in Challenging Small-Cell Lung Cancer Setting

A new study identified several T-cell antigens that are shared between tumor tissue and skin in a cohort of patients with non–small-cell lung cancer (NSCLC) who were treated with anti–programmed death 1 (PD-1) therapy. The findings could help explain the mechanisms behind autoimmune adverse effects to checkpoint inhibition.

“The autoimmune toxic effects of checkpoint inhibitors are frequent, with immune-mediated adverse effects of any grade occurring in approximately 30% of patients and toxic effects of grade 3, 4, or 5 occurring in up to 10% of patients,” wrote study authors led by Fiamma Berner, MSc, of the University of Zurich in Switzerland. “The causes of these events remain elusive.”

To examine those causes, the researchers examined a prospective cohort of 73 patients with NSCLC treated at four Swiss centers with either nivolumab or pembrolizumab. The investigators analyzed peripheral blood mononuclear cells, tumor biopsy specimens, and biopsies of the site of autoimmune skin toxic effects. Patients were a mean age of 68.1 years, and 60% were men. The 

A total of 25 patients (34.2%) developed autoimmune skin toxic effects; this was more frequent in those patients who experienced a complete remission or partial remission (68.2%) than in those with progressive or stable disease (19.6%; 

 < .001). Specifically among those with progressive disease, the rate of autoimmune skin toxic effects was 16.2%.

Patients with those toxic effects had better overall survival than those without the effects, with a hazard ratio (HR) of 0.29 (95% CI, 0.12–0.71; 

 = .004). The same was true for progression-free survival, with an HR of 0.22 (95% CI, 0.09–0.49; 

 = .001). Patients who responded to the checkpoint inhibitor therapy had an odds ratio for experiencing autoimmune skin toxic effects of 5.28 (95% CI, 1.78–15.67; 

 = .003); the authors noted that this was similar to other studies, suggesting that autoimmune adverse effects are associated with response.

The investigators reported that the sites of autoimmune skin toxic effects, as well as lung tumors, had dense infiltration of T cells. A total of nine T-cell antigens were identified that were shared between tumor tissue and skin, and these antigens were then shown to be able to stimulate CD8

“This study suggests that, during checkpoint inhibitor therapy, T cells recognizing shared lung tumor and skin antigens simultaneously target both organs,” the authors wrote. “This process is associated with the development of autoimmune skin toxic effects and likely with tumor regression as well.”

both of the University of Pittsburgh Medical Center Hillman Cancer Center, wrote that these results provide an impetus for other studies in patients experiencing a range of other autoimmune toxic effects.

“This suggests that T cells recognizing shared antigens in skin and lung tumor infiltrated both sites and supports the conclusion that the toxic effect mechanism was related to overlapping antigens in lung tumor and skin,” they wrote. “This elegant report mechanistically associated the development of skin toxic effects in patients with NSCLC treated with PD-1 blockade with detection of shared tumor-skin antigens that were subsequently shown to be immunogenic and responsible for [tumor antigen]–specific immunity at the tumor site.”

A new study identified several T-cell antigens that are shared between tumor tissue and skin in a cohort of patients with non–small-cell lung cancer who were treated with anti–PD-1 therapy.

Autoimmune Skin Toxicities Linked With Response to Immunotherapy in Lung Cancer

A 17-gene signature derived from circulating tumor cells (CTCs) was found to correlate with response to therapy and various outcomes in patients with both localized and metastatic breast cancer, according to a new study. The CTC-derived signature could help inform therapy decisions.

“Despite … increasingly effective therapeutic choices, there are few biomarkers to guide initial therapy selection and identify early responses,” wrote study authors led by 

, of the Massachusetts General Hospital Cancer Center in Boston. “As a result, treatment choices are frequently empiric, and delayed clinical ascertainment of tumor response limits the ability to rapidly define an effective regimen for an individual patient.” The new study was 

The researchers analyzed RNAseq and microarray gene expression datasets derived from normal breast tissue, breast cancer, and whole blood. From this analysis they selected 17 markers strongly expressed in breast-derived tissues but virtually absent in blood cells; the markers included genes such as 

 that are highly expressed in breast cancer, as well as others such as 

 that are implicated in endocrine signaling, and others including 

 involved in cancer growth and metastasis.

After testing this gene signature in healthy donors and each of the 17 markers in various stages of breast cancer, they applied the newly developed CTC-Score first to a cohort of 54 women with localized breast cancer treated with neoadjuvant therapy. They found that an elevated CTC-Score after at least 3 cycles of neoadjuvant therapy was associated with a higher probability of residual disease at the time of surgical resection (area under the curve, 0.83; 

In a separate cohort of 87 women with metastatic breast cancer, the researchers compared CTC-Score before initiation of new therapy and after several weeks of treatment. They found that the baseline CTC-Score was significantly associated with overall survival: those with a high baseline CTC-Score had worse overall survival, with a hazard ratio of 2.70 (95% CI, 1.15–16.7; 

 = .02), when compared with those with a low score. The median overall survival for those with a high score was 11.1 months, compared with 17.2 months in patients with a low score. Overall survival was also better in those without 

 mutations, and in those who received CDK4/6 therapy.

Furthermore, patients who had low CTC-Scores at baseline that further decreased by more than 90% after 3–4 weeks of therapy had significantly better overall survival compared with those whose score did not decrease as much or those who started with a high pretreatment score (

 = .001). “Together, these observations suggest that both pretreatment CTC burden, as well as the early treatment-induced changes in CTCs, are important prognostic factors in predicting patient outcome,” the authors wrote.

They also examined how the score could predict response in a subset of 36 patients with hormone receptor–positive disease beginning endocrine therapy. In patients with estrogen receptor–positive breast cancer, the persistence of a “resistance signature” involving 6 genes of the 17 in the full score after 3–4 weeks of treatment was associated with both shorter overall survival (

 = .008). This was consistent, the authors wrote, with inadequate suppression of estrogen receptor signaling.

“The application of ‘liquid biopsies’ to breast cancer therapeutics is rapidly evolving,” the authors wrote. “High throughput microfluidic enrichment of CTCs followed by multiplex digital RNA quantification may provide a novel and complementary strategy to monitor and guide therapy in both localized and advanced breast cancer.”

A 17-gene signature derived from circulating tumor cells was found to correlate with response to therapy in patients with breast cancer.

CTC Gene Signature Score Could Guide Breast Cancer Treatment Decisions

Alectinib offered significantly improved outcomes over standard chemotherapy in patients with advanced/metastatic 

-positive non–small-cell lung cancer (NSCLC) who had progressed on or were intolerant to crizotinib therapy, according to a new randomized trial. Alectinib also yielded more central nervous system (CNS) responses in those with CNS disease.

-positive NSCLC patients who receive first-line crizotinib progress within 1 year, often because of insufficient disease control in the CNS,” wrote study authors led by JÃ¼rgen Wolf, MD, of University Hospital Cologne in Germany. Ceritinib is currently approved for those patients, but the agent is associated with significant side effects. “Thus, a high unmet medical need exists for these patients.”

The ALUR trial randomized 107 patients to receive either alectinib (72 patients) or standard chemotherapy (pemetrexed or docetaxel; 35 patients). The trial was conducted in 13 countries in Europe and Asia; results were 

The median progression-free survival (PFS) was 9.6 months with alectinib, compared with 1.4 months with chemotherapy, for a hazard ratio (HR) of 0.15 (95% CI, 0.08–0.29; 

 < .001). A multivariate analysis adjusting for baseline factors confirmed the result, with an HR of 0.16 (95% CI, 0.09–0.30; 

 < .01). The PFS advantage was noted across subgroups divided by age, sex, baseline CNS metastases, prior radiotherapy, and other stratification factors.

At baseline, 71.0% of the full cohort had CNS disease (50 alectinib patients, 26 chemotherapy patients). The CNS response rate was significantly better with alectinib, at 54.2%, compared with 0% in the chemotherapy group (

 < .001). The time to CNS progression was longer with alectinib, with a cause-specific HR of 0.14 (95% CI, 0.06–0.36).

Following disease progression, 24 chemotherapy patients (70.6%) crossed over and received alectinib. At the time of data cutoff, the overall survival data remained immature, with an HR of 0.89 (95% CI, 0.35–2.24).

The incidence of all-grade adverse events was similar between the two treatment arms. Adverse events that occurred more frequently with alectinib than with chemotherapy included constipation, dyspnea, and increased blood bilirubin; the adverse events that occurred more commonly with chemotherapy included fatigue, nausea, alopecia, and others. Grade 3 or higher events were reported in 27.1% of alectinib patients and in 41.2% of chemotherapy patients; 5.7% of alectinib patients and 8.8% of chemotherapy patients had an adverse event that led to drug discontinuation.

“Our data support the efficacy and tolerability of alectinib, and demonstrate that alectinib shows clinically relevant superiority to chemotherapy for extra- and intracranial disease in patients who have been pretreated with crizotinib and [chemotherapy],” the authors concluded. “Alectinib has a more favorable therapeutic index than ceritinib, suggesting its preferential use in this setting.”

Alectinib offered significantly improved outcomes over standard chemotherapy in patients with ALK-positive non–small-cell lung cancer who had progressed on crizotinib therapy.

Alectinib Improves PFS, CNS Responses in Crizotinib-Treated ALK+ NSCLC

Maintenance therapy with pazopanib significantly prolonged progression-free survival (PFS) in patients with extensive-disease small-cell lung cancer (ED-SCLC), according to a new study. Substantial toxicity was seen with the therapy, however, suggesting that careful selection of patients is important.

“Despite dramatic response to first-line chemotherapy, most patients with ED-SCLC experience rapid relapse or progression during the off-therapy period,” wrote study authors led by Myung-Ju Ahn, MD, of the Sungkyunkwan University School of Medicine in Seoul. “ED-SCLC might theoretically be a good candidate for maintenance therapy, given that it is a very short interval between completion of first-line chemotherapy and its subsequent disease progression, and prolongation of this interval can eventually lead to improvement in overall survival.”

The investigators conducted a phase II study of 95 patients randomized to either pazopanib (48 patients) or placebo (47 patients); all had ED-SCLC and had not progressed after 4 cycles of etoposide plus platinum therapy. The results were 

The median ages in the pazopanib and placebo groups were 66.5 years and 67 years, respectively; most patients in both groups were male (83.3% and 91.5%, respectively) and were current or ex-smokers (89.6% and 87.2%, respectively). Most patients’ best response to etoposide/platinum therapy was a partial response (93.6% and 97.9%, respectively).

After a median follow-up of 30.1 months, the median PFS with pazopanib maintenance therapy was 3.7 months, compared with 1.8 months with placebo, for a hazard ratio (HR) of 0.44 (95% CI, 0.29–0.69; 

 < .0001). Nine patients (18.8%) receiving pazopanib achieved a PFS duration of greater than 6 months, compared with two patients (4.3%) in the placebo group (

The median overall survival was 10.6 months with the study drug and 12.9 months with placebo, for an HR of 1.14 (95% CI, 0.74–1.76; 

 = .54). The authors noted that the failure to translate the PFS benefit into an OS benefit may be related to post-study treatment; 84.4% of pazopanib patients and 97.2% of placebo patients received post-study chemotherapy.

The most common grade 3 adverse events with pazopanib included thrombocytopenia (10.4%, including one grade 4), ALT elevation (10.4%), fatigue (6.3%), hypertension (6.3%), and stomatitis (4.2%). There was only one grade 3 adverse event in the placebo group (thrombocytopenia). A total of 25 patients (52.1%) in the pazopanib group required a dose reduction due to adverse events, and 4 discontinued the treatment permanently.

The authors concluded that in spite of the positive PFS result, larger phase III trials should incorporate different designs to account for the toxicity seen in this trial. “One prerequisite for future studies can be an enrichment of study population based on predictive biomarkers that will most benefit from pazopanib maintenance therapy in terms of toxicity and efficacy,” they wrote.

Maintenance therapy with pazopanib significantly prolonged progression-free survival in patients with extensive-disease small-cell lung cancer, but with toxicity.

Pazopanib Improves PFS in Extensive-Disease SCLC, But Adds Toxicity

NY-ESO-1 SPEAR T-cell therapy showed promising results and was reasonably safe in patients with synovial sarcoma, according to a new study. The use of multiple cohorts with variations on the treatment showed that the addition of fludarabine may be important to achieving those positive results.

Outcomes are generally poor with synovial sarcoma, “highlighting the need for more novel and effective therapies,” said Sandra P. D’Angelo, MD, of Memorial Sloan Kettering Cancer Center in New York. She presented results of a study of specific peptide enhanced affinity receptor (SPEAR) T cells that recognize an NY-ESO-1 derived peptide at the Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting, held November 8–11 in Wailea, Hawaii.

The treatment involves the harvesting of lymphocytes by leukapheresis; the cells are then isolated, activated, transduced in order to express NY-ESO-1c259T, and expanded before being infused following lymphodepletion. The study included 46 patients across four cohorts with different lymphodepletion regimens. Patients in cohort 1 had high NY-ESO-1 expression, and received fludarabine and cyclophosphamide; cohort 2 had low expression and received the same regimen. Cohort 3 had high expression of NY-ESO-1 and received only cyclophosphamide, while cohort 4 had high expression and received fludarabine plus a lower dose of cyclophosphamide.

A total of 37 of the 46 patients received cell infusion. The median age across the cohorts was 33 years, and most patients had received at least two prior lines of chemotherapy. The median number of transduced cells was 2.7 × 10

The response rate (confirmed complete response plus partial responses) was 50% in cohort 1, with one complete response and five partial responses, as well as six patients with stable disease. The rate was poorer in the low-expression cohort 2, at 22%. Only one response was seen in cohort 3, where fludarabine was not used, for a response rate of 20%. Cohort 4 had three partial responses, for a rate of 27%.

The median response duration was 30.9 weeks in cohort 1, compared with only 8.4 weeks in cohort 2. In cohort 3 it was 32 weeks, and in cohort 4 it was 14 weeks. The median progression-free survival was 15 weeks in cohort 1, 13 weeks in cohort 2, 12 weeks in cohort 3, and 23 weeks in cohort 4.

“All patients experienced adverse events, and all were treatment-related,” D’Angelo said. Among the grade 3 or higher adverse events seen in more than 10% of patients were leucopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Cytokine release syndrome was reported in 16 patients, and 4 were grade 3 or higher. All events resolved with supportive care.

“Fludarabine appears to be required for optimal efficacy,” D’Angelo said, adding that one challenge moving ahead is to find the most appropriate chemotherapy regimen to go along with infused T cells. “There are ongoing efforts to understand mechanisms of resistance, as well as sensitivity,” she concluded.

NY-ESO-1 SPEAR T-cell therapy showed promising results and was reasonably safe in patients with synovial sarcoma, according to a new study. The addition of fludarabine may be important to achieving those positive results.

T-Cell Therapy With Fludarabine Active in Synovial Sarcoma

The pharmaceutical company Novartis has submitted an application to the US Food and Drug Administration (FDA) to extend the indications for its chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah). The application is for its use in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant.

“The data show this therapy could change the treatment paradigm for patients with relapsed/refractory DLBCL,” said Stephen Schuster, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, according to a 

CAR T-cell therapies have started to gain approvals in recent months. Tisagenlecleucel was first 

 at the end of August for treatment of pediatric and young adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), and in October the FDA 

 axicabtagene ciloleucel (Yescarta) for use in patients with de novo and transformed large B-cell lymphoma and high grade B-cell lymphoma in adults who failed or relapsed following two or more prior therapies.

The new application for use in DLBCL is based on results of the phase II 

, a multi-center trial being conducted in 10 countries including the United States, Canada, Japan, Australia, and in Europe. The primary analysis results of the trial will be presented at the American Society of Hematology annual meeting, to be held December 9–12 in Atlanta.

“We’ve seen durable complete responses in patients who previously relapsed or were refractory to prior therapies, and this second filing is a significant step toward realizing its potential for even more patients who are currently battling fatal blood cancers,” Schuster said. The global head of drug development and chief medical officer for Novartis, Vas Narasimhan, added that the good response rates seen in the JULIET trial show the therapy “has the potential to transform treatment for these patients.”

CAR T-cell therapy involves tailoring the agent specifically to each patient. T cells are drawn from the patient, and then genetically modified to specifically target cancer cells. In other trials involving tisagenlecleucel, cytokine release syndrome (CRS) was a significant adverse effect; its previous approval included a 

 to mitigate the risks of CRS and other neurologic toxicities.

Novartis has submitted an application to the FDA to extend the indications for its CAR T-cell therapy tisagenlecleucel (Kymriah) for its use in adult patients with relapsed or refractory diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplant.

Developer Applies for Use of CAR T-Cell Therapy in DLBCL

The second-generation EGFR tyrosine kinase inhibitor (TKI) dacomitinib significantly improved progression-free survival over gefitinib as a first-line therapy for 

 mutation–positive non–small-cell lung cancer (NSCLC), according to a randomized phase III trial.

First-generation EGFR TKIs including gefitinib and erlotinib are reversible inhibitors that selectively target EGFR; the newer generation of agents, including dacomitinib and afatinib, are irreversible and have activity against EGFR/HER1, HER2, and HER4.

“The advantages of second-generation EGFR TKIs as first-line therapy for patients with 

positive NSCLC have been clearly shown against chemotherapy but, when studied head-to-head against a first-generation TKI, the benefits were unclear,” wrote study authors led by Yi-Long Wu, MD, of the Guangdong Academy of Medical Sciences in Guangzhou, China.

The new ARCHER 1050 trial was an international, multi-center, phase III study that randomized 452 patients with newly diagnosed NSCLC and one 

 mutation. Patients received either dacomitinib (227 patients) or gefitinib (225 patients), and the median follow-up period was 22.1 months. Results were 

Patients were well matched between the groups. Most patients were never-smokers (65% in dacomitinib group, 64% in gefitinib group), and most had stage IV disease at screening (81% in both groups).

At the end of the follow-up period, 60% of dacomitinib and 80% of gefitinib patients had progressed. The median progression-free survival was 14.7 months with dacomitinib compared with 9.2 months with gefitinib, for a hazard ratio for progression of 0.59 (95% CI, 0.47–0.74; 

 < .0001). At 24 months, the progression-free survival rates were 30.6% with dacomitinib and 9.6% with gefitinib.

Response rates were similar between the groups, but duration of response was longer with the study drug than with gefitinib. Based on investigator assessment, those who responded in the dacomitinib group had a duration of response of 15.9 months, compared with 9.2 months with gefitinib (

Overall survival data was not yet mature, with 33% of dacomitinib patients and 40% of gefitinib patients having died at the time of data cut-off.

Several grade 3/4 adverse events occurred more frequently with dacomitinib than with gefitinib. These included dermatitis acneiform (14% with dacomitinib vs none with gefitinib) and diarrhea (8% vs 1%). Raised alanine aminotransferase levels were more common with gefitinib, occurring in 8% compared with 1% of dacomitinib patients. More dacomitinib patients required a dose reduction.

“Dacomitinib treatment was superior to gefitinib with respect to progression-free survival and duration of response in the first-line treatment of patients with 

-mutation positive NSCLC and should be considered as a new treatment option for this population,” the authors concluded.

The second-generation EGFR tyrosine kinase inhibitor dacomitinib significantly improved progression-free survival over gefitinib as a first-line therapy for EGFR–positive non–small-cell lung cancer, according to a randomized phase III trial.