Extended follow-up data continue to demonstrate the efficacy and tolerability of ibrutinib (Imbruvica) in previously treated patients with chronic lymphocytic leukemia (CLL), including those with high-risk gene mutations and prognostic features, according to a poster presented at the

International Congress on Hematologic Malignancies

In the 18-month analysis of the phase III RESONATE study, which was pivotal in the full FDA approval for the BTK inhibitor, treatment with ibrutinib reduced the risk of progression or death by 89% versus ofatumumab. Additionally, despite crossover, ibrutinib improved overall survival (OS) by 52% compared with ofatumumab (HR, 0.475; 95% CI, 0.284-0.795) with an 18-month OS rate of 86% in the BTK inhibitor arm.

&ldquo;We've reported now on 18-month follow-up of the RESONATE trial, which is still relatively early, but we see that in the ibrutinib arm, 76% of patients remain progression-free on ibrutinib,&rdquo; said lead author Jennifer R. Brown, MD, PhD, director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute. &ldquo;We looked at some of the high-risk features, and within the ibrutinib arm there is presently no differences between the progression-free survival and the response rates in those high risk features.&rdquo;

The phase III study randomized 391 patients with CLL and small lymphocytic leukemia (SLL) in a 1:1 ratio to either ibrutinib (n = 195) or ofatumumab (n = 196). Oral ibrutinib was administered at 420 mg daily and intravenous ofatumumab was administered initially at 300 mg in the first cycle followed by 2000 mg in 11 doses over 24 weeks. Following an interim analysis, the study was unblinded and 123 patients (63%) in the ofatumumab arm crossed over to receive ibrutinib.

Patient characteristics were balanced between the two arms. The median age of patients was 67 years, and approximately 40% were &ge;70. Patients in the ibrutinib arm received a median of 3 prior therapies, whereas those in the ofatumumab arm had received a median of 2 prior therapies. Del17p and Del11q were present in a third of patients each.

was unmutated in 73% of those in the ibrutinib arm and for 63% in the ofatumumab group.

Median progression-free survival (PFS) in the ibrutinib arm was not reached compared with 8.1 months with ofatumumab (HR, 0.106; 95% CI, 0.075-0.151;

<.0001). The 18-month PFS rate was 76% with ibrutinib versus 8% with ofatumumab (

The objective response rate (ORR) with ibrutinib was 90% versus 25% with ofatumumab (

<.0001). Overall, 13 patients achieved a complete response (CR) or CR with incomplete hematologic recovery (CRi) in the ibrutinib arm versus 1 with ofatumumab. Median time to CR/CRi with ibrutinib was 11 months.

&ldquo;The interesting feature is that most do not have complete remissions, the complete remission rate is low, but the partial remissions they have stay stable for an extended duration, and they do tend to improve over time for most of the patients,&rdquo; said Brown.

A similar PFS advantage was observed across all subgroups within the study, including gene mutations. In the del11q group, the 12-month PFS was 89% versus 8% with ofatumumab (

unmutated group, the 12-month PFS was 86% versus 12% for ibrutinib and ofatumumab, respectively (

mutations were associated with an inferior response to ofatumumab. In this group, the 12-month PFS rate with ibrutinib was 83% versus 11% with ofatumumab (

-mutated and unmutated groups, the 12-month PFS rates with ibrutinib were 85% and 91% versus 17% and 23% in the ofatumumab arm, respectively.

mutations, the 12-month PFS rate with ibrutinib was 100% versus 0% with ofatumumab, although there were too few patients to demonstrated statistical significance. Additionally, there were too few patients with

Those treated with just 1 prior therapy experienced a significantly better response with ibrutinib versus those treated with >1 prior therapy (HR, 3.294; 95% CI, 1.019-10.65;

= .0348). The ORR with ibrutinib in those who received 1 prior therapy was 100% versus 81% and 79% for those treated with 2 or &ge;3 prior therapies, respectively (

Dose reductions due to adverse events (AEs) were required for 8% of patients in the ibrutinib arm, and 7% discontinued ibrutinib due to AEs. The majority of AEs reported in the ibrutinib arm were grade 1 in severity. The most frequently reported bleeding AEs with ibrutinib, which were primarily grade 1, were an increased tendency to bruise, petechiae, and contusion.

There was one event each of grade 3 epistaxis and spontaneous hematoma and one grade 4 subdural hematoma. Atrial fibrillation occurred in 7% (3.6% grade 3) and hypertension occurred in 12% of patients (6.2% grade 3) treated with ibrutinib. Additionally, patients experienced grade 3/4 thrombocytopenia, pneumonia, and neutropenia.

&ldquo;Ibrutinib is a highly effective therapy in refractory CLL. It is generally well-tolerated, with about 20% of patients going off for various reasons, but many patients stay on and have extended disease control,&rdquo; said Brown.

Ibrutinib has gained several indications for patients with CLL/SLL. Most recently, the FDA approved frontline ibrutinib as a treatment for patients with CLL. The agent is also specifically indicated for patients with pretreated mantle cell lymphoma and Waldenstr&ouml;m's macroglobulinemia.

Brown JR, Pagel JM, Hillmen P, et al. Updated analysis of the efficacy of ibrutinib vs. ofatumumab in genetic subgroups and overall safety in the phase 3 RESONATE trial in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 20th Annual International Congress on Hematologic Malignancies; March 1820, 2016; Miami Beach, FL. Poster #386.

Articles

Clinical Articles

Extended follow-up data continue to demonstrate the efficacy and tolerability of ibrutinib in previously treated patients with chronic lymphocytic leukemia, including those with high-risk gene mutations and prognostic features.

Extended RESONATE Data Illuminates Ibrutinib's Benefits in High-Risk CLL

The experimental targeted therapy entrectinib demonstrated a dramatic response in a patient with metastatic mammary analog secretory carcinoma (MASC), which is a rare form of salivary gland cancer, according to a case report published in

In the report, a 34-year-old female patient with

rearranged MASC that had progressed following multiple lines of prior treatment, including chemotherapy and crizotinib, was given entrectinib in a phase I study. She experienced a dramatic response to entrectinib, with an 89% reduction in tumor burden. The patient is still alive, and has gone on to other therapy after 10 months on entrectinib, according to the lead author of the article Alexander Drilon, MD, attending oncologist at Memorial Sloan Kettering Cancer Center.

MASC is a novel form of cancer identified in 2010, which can be mistaken for acinic cell carcinoma (ACC), a slow-growing salivary gland tumor.

In fact, the patient in the case study was initially misdiagnosed with ACC.

The patient initially presented in January 2006 with a growing parotid mass, and surgery revealed a stage 3 cancer. The surgical margins were microscopically involved with tumor, and the patient received postoperative radiation. In August 2011, she was diagnosed with metastases to the lung, pleura, mediastinum, and chest wall.

Treatment continued with two palliative surgeries, and three different forms of chemotherapy. A surgery in February 2013 revealed a carcinoma that was morphologically similar to the patient&rsquo;s initial salivary tumor, at which point next-generation sequencing was performed, revealing that the cancer expressed an

fusion. The tumor was then reclassified as MASC.

The patient was initially treated with crizotinib (Xalkori), a multikinase inhibitor that has modest in vitro activity against Trk. Imaging indicated a 2% reduction in her disease burden at 3 weeks, and a 19% reduction at 10 weeks. However, the disease progressed by week 18, and she was enrolled in the phase I STARTRK-1 trial of entrectinib in rare forms of cancer characterized by NRK, ROS1 and ALK molecular alterations (NCT02097810).

A dramatic response followed, with her reduction in tumor burden topping out at 89% after 21 weeks. After 7 months on entrectinib, the patient had developed a solitary lung tumor, but she was kept on therapy. After 10 months on treatment, the patient had developed several other lung nodules, characterized by a novel

G623R mutation, the case report said. Entrectinib was discontinued.

&ldquo;We&rsquo;re starting to find these targets, such as gene fusions, in small slices of the pie across different cancers, such as MASC, and it becomes very difficult to mount a clinical trial against a target you might find in 1% of cases,&rdquo; said Drilon. &ldquo;So we&rsquo;ll select patients for a study regardless of their cancer type, as long as they have the appropriate targeted mutation.&rdquo;

The STARTRK-1 trial is an example of this type of study. In addition to the patient with MASC, findings have also been presented for patients with nonsmall cell lung cancer, colorectal cancer, and other tissue types. While STARTRK-1 is ongoing, a similar phase II basket study of entrectinib was initiated in September 2015, STARTRK-2. This study will enroll subjects with not only NTRK rearrangements, but also ROS1 and ALK rearrangements.

&ldquo;In targeted therapy, a phase II study could potentially be your pivotal study,&rdquo; explained Jacob Chacko, MD, CFO of San Diegobased Ignyta, which is developing the drug. &ldquo;There are a number of targeted therapies that have benefited from accelerated approval timelines by the FDA, including crizotinib for lung cancer and certain hedgehog inhibitors for basal cell carcinoma.&rdquo;

&ldquo;Given that entrectinib demonstrated responses across multiple tumor types in the Phase I study, we felt confident designing the Phase 2 study as a basket study with several different arms. Each basket is defined by the combination of a target of interestNTRK, ROS, and ALK&mdash;with a histology of interest&mdash; NSCLC, colorectal, and all others,&rdquo; he said, noting that MASC falls into the &lsquo;other&rsquo; category. &ldquo;Each basket of drug target and tumor histology could enroll at different speeds, and could be considered independently from the other baskets for purposes of a potential registration,&rdquo; Chacko said.

Enrollment of MASC patients may face certain challenges, not only because the disease is rare but also because it is so frequently misdiagnosed. For example, a retrospective review of ACC cases at The Johns Hopkins Hospital found that 11 of 14 extraparotid ACCs were marked by a genetic translocation, and therefore reclassified as MASC.

While MASC, like ACC, has been described as a &ldquo;low-grade&rdquo; malignancy, findings that it responds to targeted therapies like entrectinib might make proper diagnosis important, from both a clinical and research perspective.

&ldquo;One of the recommendations of the paper is that if you have a case of ACC or suspected MASC you should get a comprehensive molecular profiling done via next-generation sequencing,&rdquo; said Drilon. &ldquo;It&rsquo;s worth it because not all fusions or other drivers can be detected easily by older generation sequencing or assays.&rdquo;

Molecular analysis may be even more important, because the same mutations suspected of being drivers in MASC are also implicated in a number of other, seemingly unrelated, cancers. For example, another case study published last fall described a dramatic response, followed by acquired resistance, to entrectinib, in a metastatic CRC patient characterized by a

Another participant who showed a dramatic response to entrectinib was a 46-year-old patient with NTRK1-rearranged NSCLC who participated in STARTRK-1.

That patient had brain metastases, and was last described at 2015 European Cancer Congress.

rearrangements have also been identified in thyroid cancer and sarcoma, among other malignancies, according to the case study published this month in the

&ldquo;In the old days, they might do a combination of FISH, realtime PCR, and immunohistochemistry, but the beauty of nextgeneration sequencing, like our in-house assay, is that you can test for more than 400 markers,&rdquo; said Drilon. &ldquo;And the more people who adopt comprehensive molecular profiling in the community, the more quickly we can accrue patients in these trials.&rdquo;

The phase II STARTRK-2 study began enrolling in the fall of 2015. The last update on the phase I STARTRK-1 study was presented at the European Cancer Congress (ECC) in September 2015, and another update is anticipated at the AACR meeting coming up in New Orleans at the end of April. This update will discuss not only STARTRK-1 but also ALKA, the European phase I counterpart. Last year&rsquo;s ECC presentation described a response rate of 72% in 18 patients who had not previously received a ALK- or ROS1-inhibitor, across a variety of solid tumors with NTRK, ROS1, or ALK rearrangements.

Drilon A, Li G, Drogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC) [published online February 15, 2016].

Bishop J, Yonescu R, Batista D, et al. Most Nonparotid &ldquo;Acinic Cell Carcinomas&rdquo; Represent Mammary Analog Secretory Carcinomas.

Russo M, Misale S, Wei G, et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer.

Farago A, Le L, Zheng Z, et al. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

Siena S, Drilon A, Ou S, et al. Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements. Slides presented at ECCO/ESMO, Sept. 25-29, 2015.

http://ignyta.com/wp-content/uploads/2015/10/ESMO- 2015-entrectinib_F.pdf

The experimental targeted therapy entrectinib demonstrated&nbsp;a dramatic response in a patient with metastatic&nbsp;mammary analog secretory carcinoma (MASC), which is<br />
a rare form of salivary gland cancer.

Entrectinib Shows Dramatic Response in Rare Salivary Gland Tumor

The high level of efficacy observed with the combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone in the phase III SWOG S0777 study significantly changed the frontline treatment paradigm for patients with multiple myeloma, according to Shaji Kumar, MD, at the

&ldquo;This is the first time in the newly diagnosed setting that we&rsquo;ve been able to show an improved overall survival, and I think that is very important,&rdquo; said Kumar, professor of Medicine, Mayo Clinic. &ldquo;The SWOG study showed that there was an overall survival improvement seen using the triplet, and I think increasingly the field is moving toward that being the defacto combination for initial treatment.&rdquo;

The phase III study randomized 473 patients with untreated multiple myeloma to receive bortezomib plus lenalidomide and dexamethasone (n = 243) or lenalidomide and dexamethasone alone (n = 230). Those enrolled did not intend to receive immediate autologous stem cell transplant following progression.

Median progression-free survival (PFS) with the bortezomib triplet was 43 months versus 30 months with lenalidomide and dexamethasone alone (HR, 0.712; 96% CI, 0.560-0.906; one-sided

= .0018). The median overall survival (OS) was 75 months in the bortezomib arm compared with 64 months for the doublet (HR, 0.709; one-sided&nbsp;

After more than 72 months of follow-up in some cases, 72.3% of patients remained alive in the bortezomib arm versus 58.6% with the doublet. The complete response (CR) rates were 15.7% and 8.4%, with bortezomib and without, respectively. The overall response rate (ORR) was 81.5% with the triplet and 71.5% for the doublet.

The triplet is associated with peripheral neuropathy and cytopenia, which were expected with the addition of bortezomib, says Kumar. Dose modification should be considered, if toxicities become unmanageable, he advised.

Overall, the addition of bortezomib was shown to cause grade &ge;3 neuropathy in 24% of patients versus 5% with the doublet (

<.0001). The most frequently occurring grade &ge;3 hematologic adverse events (AEs) with and without bortezomib, respectively, were lymphopenia (23% vs 18%), neutropenia (19% vs 21%), thrombocytopenia (18% vs 14%), leukopenia (14% vs 16%), and low hemoglobin (13% vs 16%).

&ldquo;With the triplet combination, obviously there is more toxicity, but it seems to be easily managed,&rdquo; says Kumar &ldquo;The benefits far out weigh the risks associated with it.&rdquo;

Now that the groundwork has been laid, other proteasome inhibitor (PI)-based triplet therapies could be utilized in the frontline setting. Recently, the oral PI ixazomib (Ninlaro) gained FDA approval in combination with lenalidomide and dexamethasone as a second-line option for patients with multiple myeloma. Additionally, the PI carfilzomib (Kyprolis) is approved in the relapsed/refractory setting.

The phase III ENDURANCE trial is currently enrolling participants to partially answer the question of which PI to use in the frontline setting. In this trial, the carfilzomib triplet will be compared with the bortezomib triplet for newly diagnosed patients. The study plans to enroll 756 participants with an estimated primary completion date of May 2016. This study will also examine whether limited or indefinite maintenance therapy with lenalidomide is superior (NCT01863550).

&ldquo;I think by using combinations of these novel agents we can achieve very deep remissions, deeper than what we have seen in the past,&rdquo; Kumar said. &ldquo;We can control the disease much faster. We have decreased the proportion of patients who die very early after prognosis because of complications. Overall we&rsquo;ve improved better overall survival by maintaining better performance status. Patients are living longer than they used to.&rdquo;

In addition to the SWOG S0777 study and frontline triplet therapy, Kumar also mentioned the potential impact of novel agents in the frontline setting, such as the monoclonal antibodies daratumumab (Darzalex) and elotuzumab (Empliciti). Both of these agents were approved in late 2015, and each has a different mechanism of action. Clinical trials are currently accruing patients to investigate these therapies in the frontline setting, said Kumar.

&ldquo;All of these new drugs are going to find their way up to the newly diagnosed patient population,&rdquo; he said.

Despite so many new agents on the horizon, many challenges still remain in multiple myeloma, Kumar said. The length of maintenance therapy, optimal agents for consolidation, and the role of stem cell transplant still needs to be further evaluated, along with a growing need for biomarkers to determine which patients will benefit from treatment. Despite the already accelerated pace, Kumar expects advancement in myeloma to continue as rapidly as they have in the past few years.

&ldquo;I think we will continue to make good progress,&rdquo; he said. &ldquo;Patients are getting deep responses and living longer and longer. I think we will start looking at even more individualized therapy as we continue to better understand the biology of this disease.&rdquo;

Durie B, Hoering A, Rajkumar V, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): Results of the randomized phase III trial SWOG S0777. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 25.

The high level of efficacy observed with the combination of bortezomib, lenalidomide, and dexamethasone in the phase III SWOG S0777 study significantly changed the frontline treatment paradigm for patients with multiple myeloma.

Frontline Myeloma Therapies Undergoing Dramatic Transformation

The addition of Yttrium-90 (Y-90) resin microspheres (SIR-Spheres) to standard frontline FOLFOX-based chemotherapy with or without bevacizumab significantly improved liver-specific progression-free survival (PFS) for patients with liver metastatic colorectal cancer (CRC); however, PFS at any site, the primary endpoint of the study, was not changed with the addition of liver-directed therapy, according to data from the phase III SIRFLOX study published in the

PFS at any site was conceived as a proxy for a cure; however, the minor advantage seen in those who received selective internal radiation therapy (SIRT) along with chemotherapy was too small to be statistically significant. In the SIRT arm, patients experienced a median PFS of 10.7 months compared with 10.2 months in those who received chemotherapy alone (HR, 0.93; 95% CI, 0.77-1.12;

However, shortcomings in the study may have confounded the main findings, as the trial seemed plagued by a large number of confounding factors and a shifting trial design. Ultimately, only 84% of patients allocated to receive SIRT actually got therapy that aligned with the protocol, including 7.7% of patients (n = 19) with bilobar disease who only received SIRT in one lobe of the liver and 7.9% of patients (n = 21) who were randomized to combination therapy but did not receive SIRT at all. Additionally, the percentage of patients with an intact primary tumor was unexpectedly high, at around 45%, which may have been impacted by the international design of the study.

Despite these shortcomings, there was, however, a substantial benefit seen for PFS in the liver, and this increase was highly statistically significant. Those in the arm that received SIRT plus chemotherapy enjoyed a median liver-specific PFS of 20.5 months compared with 12.6 months for those who received chemotherapy alone (HR, 0.69; 95% CI, 0.55-0.90;

The SIRFLOX study sought to validate earlier findings from 2001 that showed an improvement in overall survival (OS) with SIRT plus floxuridine. In SIRFLOX, 530 patients were enrolled across the globe between October 2006 and April 2013. All patients were previously untreated for metastatic CRC, and were considered to have unresectable liver metastases when the study was initiated.

In addition to missing the primary endpoint, the study also did not show a significant increase in the number of liver resections. Of the patients in the arm that received SIRT, 38 (14.2%) went on to have a liver resection compared with 36 patients (13.7%) of those in the control arm.

SIRFLOX is the first of three randomized controlled trials in a preplanned combined analysis of SIRT&rsquo;s impact on OS. SIRFLOX, FOXFIRE, and FOXFIRE Global have accrued a total of 1103 patients. Combined analysis of OS data from these three trials will be examined in 2017.

To gain further insight into the findings,

spoke with Navesh K. Sharma, DO, PhD, US lead investigator of the SIRFLOX trial and one of the coauthors on the JCO paper. Sharma is the section chief of radiation oncology and associate professor at Penn State Health St Joseph Medical Center in Reading, Pennsylvania.

What are the main findings from the study?

The biggest message from the study is that SIRT can be given safely, because patients in both arms of the study were able to get the same chemotherapy. A lot of chemotherapy drugs are processed through the liver, and traditionally people were concerned that SIRT would damage the liver enough that chemotherapy would not be possible.

What are your thoughts on PFS at all sites as a primary endpoint?

I was not involved in the design of this study, but that endpoint in some ways was doomed to fail from the start. Development of new lung or bone metastasis was a failure of the endpoint, but it&rsquo;s not surprising that people failed elsewhere than the liver. Technically, it was a failure of the systemic chemotherapy.

Could the chemotherapy used in this trial have been a confounding factor?

they were not using the chemotherapy regimen that is currently used now. No oxaliplatin was involved. In general, the OS for stage 4 disease has increased from 6 months to 2 years, which is what we normally quote patients today. It&rsquo;s a huge jump.

Even more recently, the original plan for the SIRFOX study didn&rsquo;t have bevacizumab, because it was not standard of care when the study was planned, so that was added on later. Which patients are ideal for SIRT? Generally, my paradigm in treating patients with SIRT is that they have to be patients with liver-predominant metastases. However, if they already have significant disease progression elsewhere, studies have shown that even in the salvage setting, SIRT helps.

What is the importance of liver-specific PFS?

Usually the liver is the first site of metastases, and it also limits how much chemotherapy they can get. If you think about people with colorectal cancer, it&rsquo;s not the colorectal cancer or the lung metastases that kill them; lots of times it&rsquo;s the liver.

How have surgical approaches to this disease become more aggressive in recent years?

Surgeons have more laparoscopic and robotic-assisted surgical processes available. The data shows that controlling the liver metastases early gives patients a much longer survival time, especially if the liver metastases can be removed, because when the liver starts failing, you have to reduce the dose of chemotherapy.

One of the secondary endpoints on the study was to have more patients go to resection. But one of the reasons it didn&rsquo;t make it was that a lot of the surgeons had some discomfort, although there is more literature coming out that says it is safe to do liver resection following chemotherapy and radiation. The threshold for statistical significance for unplanned exploratory analyses was set as a

That was one of the robust aspects of study: the statistics were very robust. When you think of how many countries and institutions were involved, you have to have very stringent mechanisms when you go into it. We were looking at surgeon preference over four continents. Some were in smaller community centers, and not everybody had a dedicated tumor board, so it was not always possible to have a surgeon who was willing to operate afterward.

In the past, it&rsquo;s been found that different countries have different levels of resection. We&rsquo;ll be looking at some of the numbers again over the next few meetings, such as for resections, and we might be surprised in England.

van Hazel AG, Heinemann V, SHarma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer [published online February 22, 2016].

Navesh K. Sharma, DO, PhD, discusses the addition of Yttrium-90 resin microspheres to standard frontline FOLFOX-based chemotherapy with or without bevacizumab in patients with liver metastatic colorectal cancer. 

Shortcomings in SIRFLOX Design May Have Skewed PFS Findings

A number of approaches have been explored over the past 20 years in the search for a potential cure for cancer. There have been times when this cure seemed attainable, as was proclaimed across the covers of magazines like

. In many instances, those hopes did not pan out; however, this time, it is different. With the advent of immunotherapy, the possibility of curing some patients is becoming reality. It has been a roller coaster, but the latest advances are truly exemplified in melanoma, where there have been numerous FDA approvals.

One of the newly approved therapies, talimogene laherparepvec (T-VEC), represents the first in a class of therapies known as oncolytic viruses. Traditionally, viruses have been thought of as our enemies. Now, however, we are discovering they are powerful allies. This connection makes sense, since viruses are associated with the most powerful immune responses.

The FDA approved T-VEC in October 2015, based on findings from the phase III OPTiM study. The pivotal phase III trial with T-VEC randomized 436 patients with advanced melanoma. Two-thirds of the patients received T-VEC and one-third received a control, which, in this case, was recombinant GM-CSF. This was selected as the control, because GM-CSF is actually part of T-VEC and, at the time that this trial was initiated in 2008, there was some evidence that GM-CSF might have some activity in both stage III and stage IV melanoma. The study was designed to look at durable response rate (DRR), which meant that patients needed to achieve an objective response and then that response had to be maintained for 6 months or longer. In a final readout of the study, the DRR was 16.3% with T-VEC compared with 2.1% with GM-CSF. The objective response rate was 26.4% with T-VEC and 5.7% with GM-CSF.

The approval of T-VEC opens up the field to other virus-based therapies, and it allows for combination studies. In phase II studies, biopsy from some of the T-VEC injected lesions showed evidence of melanoma-specific CD8 T cells along with a decrease in regulatory T cells and myeloid-derived suppressor cells. This suggests a local immune response. Studies are now looking at T-VEC with immune checkpoint inhibitors, such as pembrolizumab and ipilimumab. In general, the field of immunotherapy has progressively moved toward combination strategies, such as these.

With the quest for precision immunology, biomarker discovery is of the utmost importance. Once implemented, biomarkers may help patients and physicians select the most promising therapeutic option while avoiding treatment strategies that are unlikely to work. For T-VEC specifically, there are a number of studies ongoing looking at viral shedding and the induction of the immune response. For the PD-1 inhibitors, several clinical trials have reported an association between clinical benefit and tumor cell expression of PD-L1, the ligand for PD-1. Additionally, mutation load has shown great promise at predicting responses.

By working together, the potential for clinical benefit in patients with cancer is increasingly bright.

Moving Toward a Cure With Immunotherapy

With nearly a dozen new PI3K and BTK inhibitors currently in development for patients with relapsed chronic lymphocytic leukemia (CLL) it is challenging to know which therapies are truly &ldquo;next-generation&rdquo; agents and which are &ldquo;me too&rdquo; products, according to a presentation by Susan O'Brien, MD, at the

Despite this ongoing hurdle, a number of therapies stand out from the pack, by offering higher efficacy or toxicity advantages. In the PI3K class, TGR-1202 has shown promising efficacy with a superior toxicity profile compared with idelalisib (Zydelig). Additionally, the BTK inhibitor acalabrutinib (ACP-196) has shown promising early signs of activity along with impressive pharmacokinetic data and a better safety profile compared with ibrutinib (Imbruvica).

&ldquo;This is really an exploding field in CLL and B-lymphoid malignancies. There are multiple PI3K and BTK inhibitor agents in clinical trials,&rdquo; said O'Brien, associate director, Clinical Science Medical Director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research, Chao Family Comprehensive Cancer Center, University of California at Irvine. &ldquo;I think the big question is, are they really next-generation? There are a lot of trials now looking at those who failed BTK or PI3K inhibitors. It's interesting times.&rdquo;

The PI3K inhibitor that is furthest along in development is duvelisib (IPI-145), explained O'Brien. Although this agent targets both PI3K delta and gamma, at the current dose under development, it primarily inhibits just the delta isoform, she noted.

the objective response rate (ORR) with duvelisib was 57% at 25-mg twice daily. This response rate did not include partial responses (PR) with lymphocytosis, which are common with the B-cell signaling inhibitors, noted O'Brien. Once these are added, the ORR was closer to 80%, she explained.

The progression-free survival (PFS) was not reached with the 25 mg twice-daily dose of duvelisib versus 15.7 months across all doses in pretreated patients with CLL. The 24-month PFS rate at the 25 mg dose was 59%. Similar data were demonstrated in the

Across the study, duvelisib showed a similar toxicity profile to the already FDA-approved PI3K inhibitor idelalisib (Zydelig), said O'Brien. Across all doses, pneumonia occurred in 15 patients, with 7 discontinuing therapy as a result.

A number of studies continue to assess duvelisib in various combinations, including ofatumumab (NCT02004522), fludarabine, cyclophosphamide and rituximab (NCT02158091), and with obinutuzumab (NCT02292225) for patients with relapsed CLL. The study comparing the drug with ofatumumab is meant to support an FDA approval and is expected to complete later in 2016, according to O'Brien.

Compared with duvelisib and idelalisib, the next-generation PI3K-delta inhibitor TGR-1202 has a unique molecule structure that provides the agent with a differentiated safety profile, notably the absence of hepatic toxicity, noted O'Brien.

In a dose escalation study of 17 patients with CLL,

the response rate in the lymph nodes with TGR-1202 was 94%. The ORR was 59%, which consisted entirely of partial responses. The median PFS with the PI3K inhibitor was 24 months.

Interestingly, with TGR-1202 there were no incidences of colitis and only 4% of patients experienced an AST/ALT increase, half of which were grade 3/4 events. Seven percent of patients discontinued due to adverse events (AEs). The presumed thinking is that colitis is an on-target effect of PI3K inhibition; however, these results would call this theory into question, O'Brien said.

&ldquo;Discontinuations are rare, and if you look at the transaminase elevation that appears to be much less,&rdquo; she said. &ldquo;This looks to be very interesting, and I say stay tuned to see what happens, and to see how this adjusts our thinking with the PI3K inhibitor toxicity profile.&rdquo;

TGR-1202 is being explored in a number of clinical trials for patients with CLL, including in combination with ibrutinib in the relapsed setting (NCT02268851). Additionally, the combination of TGR-1202 and the CD20 inhibitor ublituximab is being compared with obinutuzumab and chlorambucil in the relapsed and frontline setting (NCT02612311). TGR-1202 plus ublituximab is also being looked at with or without ibrutinib (NCT02006485).

&ldquo;There is a design for a pivotal trial, but it has not yet been announced,&rdquo; O'Brien added.

Another agent in development, ACP-319 (previously AMG-319), targets the delta isoform and has shown similar findings as idelalisib. Data from this study were last presented at the 2013 ASH Annual Meeting. Acerta Pharma recently acquired the agent, and an ongoing phase I study is currently exploring ACP-319 in combination with acalabrutinib for patients with CLL (NCT02157324).

&ldquo;This is an interesting study with both a PI3K inhibitor and a BTK inhibitor for patients with relapsed CLL,&rdquo; noted O'Brien.

The early phase BTK inhibitor ONO-4059 demonstrated promising signs of clinical efficacy in 2014; however, further data on this agent have not yet been reported, noted O'Brien. The ORR with ONO-4059 was 84%, including ORRs of 89% in del17p patients and 92% in a refractory population.

In December 2014, Gilead acquired exclusive rights to ONO-4059 for the treatment of B-cell malignancies and other disease. After the acquisition, Gilead renamed the drug GS-4059 and is now exploring the agent in combination with idelalisib or the SYK inhibitor entospletinib for patients with relapsed B-cell malignancies (NCT02457598).

&ldquo;Entospletinib is very well tolerated but if you look at the data the response rates are 30% to 40%, so not as effective as BTK or PI3K inhibitors in CLL,&rdquo; said O'Brien.

The second-generation BTK inhibitor acalabrutinib has shown promising early signs of activity, including pharmacokinetic studies that suggest the agent is five times more potent than ibrutinib. This added strength does not only apply to BTK but also other kinases, including Tec, which is thought to mediate certain AEs.

&ldquo;One of the potential benefits of this is that if we think some of the toxicity related to ibrutinib is from the binding to these other kinases. What you would hope is that you would have some of these toxicities being much less likely to be seen with acalabrutinib,&rdquo; said O'Brien. &ldquo;The other thing that might be potentially very favorable with this drug is that it does not inhibit platelet mediated thrombosis, which we know that ibrutinib does, and is one of the reasons for the bruising.&rdquo;

In data from a phase I/II 60-patient study,

the ORR with acalabrutinib was 95%. In the del17p population, the ORR was 100%. The median PFS was 14.3 months, with 1 fatal progression and 1 disease progression.

There were no episodes of atrial fibrillation or major bleeding events. Two percent of patients had grade 4 febrile neutropenia, and serious AEs consisted of pneumonia (10%), autoimmune hemolytic anemia (3%), and pyrexia (3%).

Following the early demonstration of efficacy and tolerability, a number of studies were initiated to explored acalabrutinib. The agent is being looked at alone or in combination with obinutuzumab versus chlorambucil and obinutuzumab (NCT02475681). The pivotal study for this agent will compare acalabrutinib directly with ibrutinib for high-risk patients with relapsed CLL (NCT02477696).

&ldquo;I would encourage you to put your patients on this trial, because one nice thing is that ibrutinib is provided for free,&rdquo; said O'Brien. &ldquo;Here, even if they get randomized to the 'control' arm, they are still getting a very good drug for free.&rdquo;

Acalabrutinib is also being explored in combination with the PD-1 inhibitor pembrolizumab (Keytruda) across CLL, multiple myeloma, and other hematologic malignancies (NCT02362035). The agent is also being explored as monotherapy across CLL treatment settings (NCT02337829).

Another early phase BTK inhibitor in development, BGB-3111, has shown early signs of activity and tolerability. In a phase I study of 14 patients with CLL,

the response rate was 93%. The AEs were similar to expectations, including bruising, petechiae, and contusion.

&ldquo;In every BTK trial, some of these people were 75 or 80 years old, we all know when you get older your skin thins. Every patient has bruising. How much is drug-related, remains unclear,&rdquo; said O'Brien. &ldquo;These data were presented very early, in fact, there is no data for durability of these responses, and this study is actually still ongoing and this is the only study for this drug right now.&rdquo;

A great deal of research still needs to be conducted before this new wave of BTK and PI3K inhibitors can be labeled either next-generation or "me too" agents, said O'Brien. A traditional next-generation agent will still be effective after a first-generation therapy has failed, she noted. Some of the benefits of these agents might be better efficacy and less toxicity, but it remains too soon to draw conclusions.

O'Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-&delta;,&gamma; Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 3334.

O'Connor OA, Flinn IW, Patel MR, et al. TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 4154.

Fegan C, Bagshawe J, Salles G, et al. A Phase I Study of the Oral Btk Inhibitor ONO-4059 in Patients with Relapsed/Refractory and High Risk Chronic Lymphocytic Leukaemia (CLL). Presented at: 19th Congress of the European Hematology Association; Milan, Italy; June 12-15, 2014. Abstract S705

Byrd JC, Harrington B, O&rsquo;Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia [published online December 7, 2015].

Tam C, Grigg AP, Opat S, et al. The BTK Inhibitor, Bgb-3111, Is Safe, Tolerable, and Highly Active in Patients with Relapsed/ Refractory B-Cell Malignancies: Initial Report of a Phase 1 First-in-Human Trial. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 832.

With nearly a dozen new PI3K and BTK inhibitors currently in development for patients with relapsed chronic lymphocytic leukemia it is challenging to know which therapies are truly "next-generation" agents and which are "me too" products.

Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL

It is impossible to traverse life without a friend or family member experiencing cancer. For many in the United States, this experience manifests as breast cancer, since 1 in 8 women are diagnosed with this disease at some point in their lifetime. As the most common cancer worldwide, screening for breast cancer is of the utmost importance.

Despite the prevalence, the US Preventive Service Task Force (USPSTF) kicked off 2016 with a controversial recommendation against screening for women under the age of 50 who are at average risk. This change, which was preceded by half a decade of debate, joined other guidelines suggesting a similar starting age, including those from the American Cancer Society (ACS).

Across guidelines, the term "average" is used to describe a woman's risk; however, many women are not unaware of their level of risk, which adds to the confusion. The group Bright Prink emphasized this point, after the ACS announced the new guidelines. To help provide important information, Bright Pink provides a helpful tool that helps women gauge their risk (

), and the group continues to recommend annual screening starting at age 40.

The success of earlier screening was showcased during the keynote address delivered by Amy Robach at the

. Robach shared her story about the importance of beginning screening at age 40, which was her age when she was diagnosed with stage II breast cancer after receiving a mammogram on live TV. Had she followed the new guidelines, her cancer may still be growing undetected today (see more, on page 24).

Each year, even in the wake of these guidelines, we are reminded prior to the month of April about the importance of cancer screening. Like clockwork a Presidential Proclamation is issued in March declaring April &ldquo;Cancer Control Month.&rdquo; This tradition was established in March 1938 and has been repeated every year since, with the latest proclamation made on March 31, 2016.

During Cancer Control Month the question that begs to be asked is, &ldquo;Why is screening being cut in the same breath that diet, exercise, and lifestyle choices are heralded as keystones in controlling cancer?&rdquo; Following the USPSTF guidelines, a joint statement from the American College of Radiology and the Society of Breast Imaging said the decision could be lethal for thousands of women. If this is truly the case, these guidelines are a step in the wrong direction toward controlling cancer.

The breast cancer guidelines in the United States need to be fixed, which can only be accomplished by those on the frontlines. We need oncologists to chime into the discussion. To contact the USPSTF, visit

The breast cancer guidelines in the United States need to be fixed, which can only be accomplished by those on the frontlines. We need oncologists to chime into the discussion.