Ben Leach

A phase III trial of the investigational monoclonal antibody necitumumab has met its primary endpoint of improving overall survival in patients who received the drug in combination with gemcitabine and cisplatin as a first-line therapy for metastatic squamous non-small cell lung cancer (NSCLC) when compared with chemotherapy alone, according to an announcement from Lilly, the drug’s manufacturer.

Lilly did not provide specific data regarding the results of the trial, but the company announced that it plans to present that data at a scientific meeting next year, and to request a review of the drug by regulatory authorities before the end of 2014.

“We are pleased with these data which represent a potential advance in treatment for patients with squamous non-small cell lung cancer, which is a difficult cancer to treat,” said Richard Gaynor, MD, vice president, product development and medical affairs for Lilly Oncology, in a statement. “If approved, necitumumab could be the first biologic therapy indicated to treat patients with squamous lung cancer.”

Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR), which is a target in several anti-cancer treatments because it sparks cancer progression, both by promoting angiogenesis, or the formation of new blood vessels for tumors, and by inhibiting apoptosis, or cell death. Recently approved therapies for non-squamous NSCLC, including afatinib and erlotinib, target specific EGFR mutations, but those drugs are used to treat patients with nonsquamous histology.

In the phase III SQUIRE trial, 1093 patients with histologically or cytologically confirmed stage IV squamous NSCLC, who had received no prior therapy for metastatic disease, were randomized to receive one of two intravenously administered regimens. Patients in the experimental arm got first-line necitumumab at a dose of 800 mg on days 1 and 8 of every 3-week cycle in combination with gemcitabine at a dose of 1250 mg/m

 on days 1 and 8 of every 3-week cycle and cisplatin at a dose of 75 mg/m

 on day 1 of every 3-week cycle. Those in the control arm received a combination of gemcitabine and cisplatin at the same doses given in the experimental arm.

Necitumumab was being investigated in two separate phase III trials. The other study, the INSPIRE trial, was designed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone. The study was discontinued in 2011 because of safety concerns over patients developing blood clots.

Lilly is also conducting a phase II study in which necitumumab in combination with paclitaxel and carboplatin is being evaluated in patients with stage IV squamous NSCLC. Previously, the drug had also been explored as a potential treatment for colorectal cancer and other solid tumors.

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A phase III trial exploring necitumumab plus chemotherapy as a first-line therapy for patients with metastatic squamous non-small cell lung cancer has demonstrated an improvement in overall survival when compared to chemotherapy alone. 

First-Line Necitumumab Improves Survival in Metastatic Squamous NSCLC

Patients with two different hematologic malignancies—chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL)&mdash;showed high response rates to therapy with the novel targeted therapy ibrutinib, further solidifying the safety and efficacy of a drug that has proven very promising in early clinical trials.

The results of both clinical trials were published in the 

Ibrutinib is a selective tyrosine kinase inhibitor of the Bruton’s tyrosine kinase enzyme, which is associated with apoptosis, cell adhesion, cell migration, and other cellular processes that can help a tumor survive. The drug also has little effect on healthy T cells. In addition to CLL and MCL, ibrutinib is being investigated in multiple myeloma, follicular lymphoma, and diffuse large B-cell lymphoma.

In the first study, a phase Ib/II trial, 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) received ibrutinib orally once daily, with 51 patients receiving a 420 mg dose and 34 patients receiving an 840 mg dose. The majority of these patients had high-risk disease and had received a median of four prior therapies.

The study found that the overall response rate (ORR) in both treatment groups was 71%, with an additional 20% of patients in the 420 mg dose arm and 15% of patients in the 840 mg dose arm experiencing a partial response with lymphocytosis. After a follow-up of 26 months, the estimated rate of progression-free survival (PFS) was 75%, and the rate of overall survival (OS) was 83% for all patients, irrespective of the dose.

Most of the side effects were grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection.

“Essentially all CLL patients respond well to ibrutinib, which lacks many of the side effects of chemotherapy and frequently produces long-lasting remissions even in patients with high-risk genetic lesions,” said John C. Byrd, MD, director of the division of hematology and a CLL specialist at the Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and one of the study co-leaders, in a statement.

In the second study, 111 patients with relapsed or refractory MCL received a daily dose of 560 mg of ibrutinib. Patients enrolled in this phase II trial were divided into two groups: those who had received ≥2 complete cycles of prior bortezomib therapy and patients who had received <2 complete cycles of the therapy, including those with no prior bortezomib therapy. ORR was the primary endpoint, with duration of response, PFS, OS, and safety serving as secondary endpoints.

The investigators observed an ORR of 68%, a complete response rate of 21%, and a partial response rate of 47%, with prior bortezomib having no effect on the rate of response. After a median follow-up of 15.3 months, the estimated median duration of response was 17.5 months (95% CI, 15.8—not reached), the median PFS was 13.9 months (95% CI, 7.0–not reached), and the median OS was not yet reached. At 18 months, the estimated rate of OS was 58%.

“This is remarkable because the last agent approved by the FDA for MCL had a 30% response rate,” says Kristie Blum, MD, associate professor of medicine, head of the OSUCCC — James lymphoma program, and senior author of the study, in a statement. “This trial suggests that ibrutinib could significantly improve the landscape of therapy options for MCL.”

The researchers said that grade 3 or higher hematologic events were infrequent. These included neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

Earlier this year, ibrutinib received three separate breakthrough therapy designations from the FDA, which helps to facilitate an expedited review process for promising drugs that demonstrate a substantial improvement over existing treatments. This designation was granted to ibrutinib for the treatment of CLL or SLL with deletion of the short arm of chromosome 17, relapsed or refractory MCL, and Waldenström’s macroglobulinemia.

			Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia [published online ahead of print June 19, 2013]. 

			Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma [published online ahead of print June 19, 2013]. 

Patients with chronic lymphocytic leukemia and mantle cell lymphoma showed high response rates to therapy with the novel targeted therapy ibrutinib, further solidifying the safety and efficacy of a drug that has proven very promising in early clinical trials.

Two Studies Show Efficacy of Ibrutinib in Hematologic Malignancies

After receiving breakthrough therapy designation from the FDA for the treatment of two B-cell malignancies earlier this year, ibrutinib has received an additional breakthrough designation for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17.

Ibrutinib is a selective tyrosine kinase inhibitor of the Bruton’s tyrosine kinase enzyme, which is associated with apoptosis, cell adhesion, cell migration, and other cellular processes that can help a tumor survive. In addition to CLL/SLL, ibrutinib is being investigated in multiple myeloma, follicular lymphoma, and diffuse large B-cell lymphoma. In February, ibrutinib received breakthrough designation for Waldenström’s macroglobulinemia and mantle cell lymphoma.

Patients with CLL with this chromosome 17 deletion (del 17p) often have poor outcomes if they receive treatment with chemotherapy.

According to the 2012 FDA Safety and Innovation Act (FDASIA), breakthrough therapy designation is assigned to drugs designed to treat a life-threatening condition when “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

The purpose of the breakthrough designation is to expedite the review process for ibrutinib for CLL/SLL by allowing for more meetings during the development process, potentially reducing the number of patients required for clinical trial enrollment, and shortening the time needed to conduct those clinical trials.

Ibrutinib is being co-developed and co-commercialized through a collaborative agreement between Janssen Biotech, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and Pharmacyclics. The manufacturers are still allowed to seek fast-track designation, accelerated approval, and priority review for ibrutinib for this indication during the review process.

“Ibrutinib continues to demonstrate promise for patients living with B-cell malignancies, and we are pleased that the FDA has recognized its potential for people living with CLL and the del17p mutation,” said Peter F. Lebowitz, MD, PhD, head of Global Oncology Therapeutic Area at Janssen, in a statement. “This third breakthrough therapy designation reflects the potential importance of ibrutinib for patients diagnosed with a 17p deletion chromosomal abnormality in CLL/SLL, and we are committed to working with Pharmacyclics and the FDA to expedite development and review of ibrutinib as quickly as possible.”

The news of the additional breakthrough designation comes on the same day that new data on ibrutinib’s effectiveness for the treatment of CLL were presented at the American Association of Cancer Research (AACR) Annual Meeting 2013, held in Washington, DC.

In the ongoing phase II study, 53 patients with CLL were divided into two cohorts, with 29 patients with del 17p and 24 patients without del 17p who were at least 65 years old. Patients received 420 mg of ibrutinib daily, and their responses were evaluated at six months and every six months thereafter until disease progression.

At 12 months, the estimated event-free survival rate was 94%. After six months, at least a 50% reduction in lymph node disease was observed in 95% of patients, with a median reduction in lymph node size of 73%. A median decrease of 82% in tumor infiltration in bone marrow was observed in patients who received a bone marrow biopsy. All patients showed a reduction in spleen enlargement, with a median reduction of 55%.

The drug was also well tolerated, with most adverse events reported as mild, with nonhematologic toxicities that were grade 3 or higher occurring in less than 13% of patients. Two patients on the study died, but their deaths were not related to the treatment.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” said Adrian Wiestner, MD, PhD, investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, MD, in a statement. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen, and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

	Wiestner A, Herman S, Mustafa R, et al. Potent single agent activity of Ibrutinib (PCI-32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study. Presented at: AACR Annual Meeting 2013; April 6—10; Washington, DC. Abstract LB-141.

After receiving breakthrough therapy designation from the FDA for the treatment of two B-cell malignancies earlier this year, ibrutinib has received an additional breakthrough designation.

Ibrutinib Receives Additional Breakthrough Designation for CLL

The compound LDK378, a highly selective inhibitor of 

, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with 

-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).

The designation was granted based on positive early data on LDK378. Initial results obtained from a phase I study showed a significant response rate in patients with 

-positive NSCLC who had progressed on treatment with or had become intolerant to crizotinib, an FDA-approved treatment for this type of lung cancer.

According to a statement from Novartis Oncology, the manufacturer of the drug, a response rate of 80% was observed in the study, which included complete response, partial response, and unconfirmed partial response to the drug. Dose-limiting toxicities reported in the study included diarrhea, vomiting, nausea, and dehydration. The results were presented at the 2012 European Society of Medical Oncology Congress in Vienna, Austria.

“LDK378 is a strong example of our research approach, which focuses on identifying the underlying cause of disease pathways,” said Alessandro Riva, MD, Global Head of Oncology Development & Medical Affairs for Novartis Oncology, in a statement. “This Breakthrough Therapy designation will allow us to collaborate more closely with the FDA and potentially to expedite the availability of an important new treatment option for patients with 

Drugs can receive a breakthrough therapy designation as part of the 2012 FDA Safety and Innovation Act (FDASIA). According to the act, drugs like LDK378 can receive the designation if the drug is designed to treat a life-threatening condition and early evidence shows that endpoints such as survival are significantly improved over existing therapies.

The act is designed to expedite the review process by allowing for more meetings to take place during the development process, potentially reducing the number of patients required to enroll in further clinical trials, and shortening the length of those trials when possible. In the case of LDK378, Novartis Oncology can still seek fast-track designation, accelerated approval, and priority review for the drug during the review process.

According to Novartis Oncology, two phase II trials are currently enrolling patients, and several phase III trials are expected to be initiated later this year. The first regulatory filing is expected in 2014.

	1. Shaw AT, Camidge R, Felip E, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Vienna, Austria: European Society for Medical Oncology; September 30, 2012. Abstract 440.

The compound LDK378, a highly selective inhibitor of ALK, has been granted "Breakthrough Therapy Designation" by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer.


Novel Compound LDK378 Receives Breakthrough Designation for ALK+ NSCLC

The investigational agent ibrutinib was granted “Breakthrough Therapy Designations” by the FDA as a singular therapy for a pair of B-cell malignancies: relapsed or refractory mantle cell lymphoma (MCL) and Waldenström’s macroglobulinemia.

Ibrutinib is a tyrosine kinase inhibitor that selectively inhibits the Bruton’s tyrosine kinase enzyme. This enzyme is associated with the regulation of apoptosis, cell adhesion, and cell migration and helps the microenvironment of the tumor survive. Currently, ibrutinib is being investigated in a number of hematologic malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Waldenström’s macroglobulinemia, and multiple myeloma.

The drug is being co-developed and co-commercialized through a collaborative agreement between Janssen Biotech, Inc. part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and Pharmacyclics.

A breakthrough therapy is a relatively new FDA designation that was enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA). The goal is to further expedite the time necessary for development and review of a new drug “to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

According to the act, this designation would allow for more meetings to take place during the development process, potentially reduce the number of patients required to enroll in further clinical trials, and subsequently shorten the length of those trials when it is appropriate. Manufacturers of these drugs are still allowed to seek fast-track designation, accelerated approval, and priority review.

“We are pleased that the FDA has granted two Breakthrough Therapy Designations for ibrutinib as the designation represents a major leap forward in accelerating drug development timelines,” said Paul Stoffels, MD, Chief Scientific Officer and Worldwide Chairman of Pharmaceuticals at Johnson & Johnson, in a statement. “We are committed to realizing the full potential of ibrutinib for patients with mantle cell lymphoma, Waldenström’s macroglobulinemia, as well as other B-cell malignancies, and will work with Pharmacyclics and the FDA to ensure the clinical development program for ibrutinib continues to move forward as quickly as possible.”

Ibrutinib’s two breakthrough designations are among the first as a result of the act. The first breakthrough designations were announced in January for two cystic fibrosis treatments from Vertex Pharmaceuticals: ivacaftor (Kalydeco) monotherapy, and a combination of ivacaftor and the investigational compound VX-809.

The investigational agent ibrutinib was granted "Breakthrough Therapy Designations" by the FDA as a singular therapy for a pair of B-cell malignancies: relapsed or refractory mantle cell lymphoma and WaldenstrÃ¶m's macroglobulinemia.

Ibrutinib Receives Breakthrough Designations for Mantle Cell Lymphoma and WaldenstrÃ¶m's Macroglobulinemia

Patients with metastatic non—small cell lung cancer (NSCLC) often experience disease progression after receiving a tyrosine kinase inhibitor (TKI) as a targeted treatment. While there is no guideline on what to do once this progression occurs, chemotherapy is often used as a second-line treatment. In a recent study, Andrew J. Weickhardt, MBBS, DmedSc, University of Colorado Cancer Center, Aurora, and colleagues examined whether local ablative therapy (LAT) plus continuation on the same TKI could be utilized as a treatment alternative in this setting.

Metastatic NSCLC patients with rearrangements of 

 have high response rates and long periods of progression-free survival (PFS) when treated with crizotinib and erlotinib, respectively. However, patients often progress after these targeted therapies are administered, due to changes in the tumor, such as the development of new kinase domain mutations in the drug target or the development of alternate oncogenic drivers. Additionally, in some cases, the drug is unable to penetrate the central nervous system and the disease will progress into the brain.

Weickhardt et al studied patients with mutations of either 

 who were subsequently treated with crizotinib or erlotinib, respectively, at the University of Colorado Cancer Center between May 2005 and December 2011. When these TKI drugs were given as initial therapy, the PFS of patients who were ALK-positive and received crizotinib was 9.0 months, and patients who were 

-mutant and received erlotinib had a median PFS of 13.8 months.

During that period, 51 patients experienced disease progression after TKI therapy. Of those patients, 25 (49%) were deemed suitable for LAT with either radiotherapy (n = 24) or surgery (n = 1) along with continuation of the same TKI therapy. After LAT, 19 of the 25 patients progressed, this time experiencing a median PFS period of 6.2 months in addition to the previous period of PFS achieved with frontline TKI therapy.

The researchers noted that a more substantial benefit was observed in patients whose disease had progressed only to the brain. There were 10 patients total in the study in which the brain was the site of first progression. In this subgroup, the median PFS with frontline TKI therapy was 10.9 months. When these patients received LAT after their first progression, the second median PFS was 7.1 months, a slightly higher period of PFS than observed in the total study population.

The authors noted that their study had limitations. The research was conducted using only patients seen at a single cancer center, so the authors suggest that while the study is encouraging, it should serve as a basis for more complete studies in the future. Additionally, the study did not use a comparator, such as chemotherapy, to determine whether continuation on TKI therapy is truly superior to chemotherapy.

“We strongly advocate that to delineate the true extent of benefit, a prospective trial is required across multiple centers with defined treatment criteria and standardized restaging technology (PET/MRI) should be used at defined intervals to minimize bias,” the authors wrote.

	Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitor in oncogene-addicted non-small-cell lung cancer. 

Local ablative therapy plus continuation on the same tyrosine kinase inhibitor could be utilized as a treatment alternative in metastatic non-small cell lung cancer.

Local Ablative Therapy Might Extend TKI Benefit in NSCLC

A phase III study of axitinib (Inlyta) as a front-line therapy for metastatic renal cell carcinoma (mRCC) did not meet its primary endpoint of demonstrating a longer period of median progression-free survival (PFS) than sorafenib (Nexavar), according to a statement released by axitinib’s manufacturer, Pfizer.

Pfizer reported that a preliminary analysis of data from the phase III AGILE 1051 trial did not show an improvement in median PFS when the two drugs were compared head-to-head. The trial enrolled more than 280 patients with mRCC who were either treatment-naïve or had progressive disease per RECIST criteria after one prior systemic first-line regimen for metastatic disease containing sunitinib, cytokines, or both. Overall, the median PFS for patients with mRCC who received axitinib was slightly higher than for those who received sorafenib, but the results were not statistically significant.

Among patients in a pre-specified subgroup with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, which is considered a good performance status, the median PFS for patients who received axitinib was higher than the median PFS observed in patients who received sorafenib, according to Pfizer. Among another pre-specified subgroup of patients with an ECOG Performance Status score of 1, considered an intermediate status, there was no difference in survival between patients who received axitinib and those who received sorafenib.

“We narrowly missed the primary endpoint in this trial,” said Mace Rothenberg, MD, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit, in a statement. “We are analyzing the study findings to determine whether further evaluation of Inlyta in specific subpopulations of treatment-naïve patients with advanced RCC would be warranted.”

An oral kinase inhibitor, axitinib is designed to selectively inhibit vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, which have been known to promote tumor progression and angiogenesis.

Axitinib was granted FDA approval in January to treat advanced RCC in patients who failed to respond to prior therapy. The approval was based on the results of a randomized, open-label, multicenter study involving 723 patients from 22 countries who had RCC and progressed despite receiving sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or a cytokine as first-line therapy. Like those in AGILE 1051, patients were randomly assigned to receive either axitinib or sorafenib.

In that study, the median PFS observed in patients who received axitinib was 6.7 months (95% CI, 6.3-8.6) compared with 4.7 months (95% CI, 4.6-5.6) for those receiving sorafenib, demonstrating a 33.5% improvement in PFS (hazard ratio [HR] = 0.665; 95% CI, 0.544-0.812; 

“We set a high bar in our Inlyta trials to understand how it compares to another VEGF-targeted therapy,” Rothenberg said. “Since approval, Inlyta has established its utility in the second-line setting where it is an important treatment option for many patients with advanced kidney cancer.”

A separate cohort of more than 200 Asian patients who were treated with axitinib or sorafenib in a second-line setting was also part of the AGILE 1051 study. The results of that portion of the cohort were originally expected to be presented at the American Society of Clinical Oncology (ASCO) meeting earlier this year, but were withdrawn and will be presented at a future medical meeting, according to Pfizer.

Several other clinical trials are underway to determine whether axitinib has treatment uses beyond those currently approved. One trial, the AGILE 1046 study, is a randomized phase II study in treatment-naïve patients with advanced RCC in which axitinib is given with or without dose titration, with overall response rate serving as the primary outcome. Data from the trial presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) demonstrated a median PFS of more than 1 year and an overall response rate of 40.2% in the treatment arm of the study.

	1. Rini BI, Grünwald V, Fishman MN, et al. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic analyses from a randomized phase II study. 

A phase III study of axitinib as a front-line therapy for metastatic renal cell carcinoma did not meet its primary endpoint of demonstrating a longer median progression-free survival than sorafenib.