Another ASCO annual meeting has come and gone, and now comes the fun part where we digest and interpret the significance of the mountains of new data presented. One of the themes that emerged from the meeting was the number of significant large, late-stage clinical trials that were showcased. In this month’s special all-ASCO issue, we highlight these practice-changers, as well as several emerging treatments that have shown great promise.

In lung cancer, nivolumab (Opdivo) has now been shown to have an overall survival benefit versus docetaxel in both nonsquamous and squamous non—small cell lung cancer, according to results from the CheckMate-057 and CheckMate-017 trials, respectively (

Nivolumab also shined in melanoma, where frontline treatment with the PD-1 inhibitor as monotherapy and in combination with ipilimumab more than doubled progression-free survival (PFS) versus ipilimumab alone in patients with advanced melanoma, according to results from the phase III CheckMate-067 trial (

Pivotal late-stage study data for several hematologic malignances were also presented. In the phase III HELIOS study, adding ibrutinib (Imbruvica) to standard bendamustine and rituximab reduced the risk of disease progression in patients with pretreated chronic lymphocytic leukemia (

Patients with relapsed indolent non-Hodgkin lymphoma experienced a doubling of PFS when treated with a combination of the anti-CD20 agent obinutuzumab (Gazyva) and bendamustine compared with bendamustine alone, according to findings of the phase III GADOLIN study (

In multiple myeloma elotuzumab and carfilzomib (Kyprolis) were shown to improve PFS versus standard treatments in the phase III ELOQUENT-2 and ENDEAVOR trials, respectively (

Adding palbociclib (Ibrance) to standard fulvestrant more than doubled PFS in pretreated patients with HR-positive, HER2-negative breast cancer in the phase III PALOMA-3 trial (

Goods news was also presented in soft tissue sarcoma (STS), where both eribulin (Halaven) and trabectedin were shown to improve outcomes in the difficult-to-treat disease (

The meeting was not without its usual share of exciting results for emerging treatments, as well, and we cover several in this issue, including atezolizumab (MPDL3280A) and MEDI4736 in lung cancer, nivolumab in hepatocellular carcinoma, and pembrolizumab (Keytruda) in head and neck cancer (

The meaning of these and other ASCO data will continue to be interpreted in the months ahead and we look forward to covering the ongoing developments for you. As always, thank you for reading. 

Articles

Another ASCO annual meeting has come and gone, and now comes the fun part where we digest and interpret the significance of the mountains of new data presented.

Late-Stage Studies Star at ASCO 2015

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

		John Theurer Cancer Center at Hackensack University Medical Center

Although the ASCO annual meeting has become quite a spectacle (32,000 attendees this year!), it has retained its core purpose of providing a unique platform for oncologists to interact and exchange the latest practice-changing research. At this year’s meeting, there was again a great feeling of palpable excitement among oncologists, as we are definitely witnessing the dawn of a new era in cancer care. It is obviously beyond the scope of this column to summarize all of the significant ASCO data, but the few highlights below will help illustrate some of the ongoing dramatic changes in the field.

Likely the most striking research was the confirmation of the impact of checkpoint inhibitors across several cancer subtypes. First, a randomized trial in previously treated, advanced, squamous cell non—small cell lung cancer (NSCLC) comparing nivolumab to chemotherapy (docetaxel), showed significant improvement in both response rate (20% vs 9%) and survival (median overall survival [OS], 9.2 vs 6.0 months and 1-year OS, 42% vs 24%), regardless of PD-L1 expression level. Nivolumab was also shown to improve survival versus docetaxel in pretreated nonsquamous cell NSCLC (median OS, 12.2 vs 9.4 months and 1-year OS, 50.5% vs 39.0%).

In melanoma, data presented at the plenary session showed that the combination of two checkpoints inhibitors—nivolumab (anti—PD-1) and ipilimumab (anti– CTLA-4)&mdash;versus either agent alone was impressively superior for both median progression-free survival (11.5 vs 2.9 months for ipilimumab alone) and overall response rate (57% versus 19%). Though the combination was more toxic, this was manageable and the benefit was even seen in PDL1– negative tumors.

Not surprisingly, checkpoint inhibition is being explored as well in other tumors with encouraging data already in head neck cancers and hepatocellular carcinoma, as well as hematological malignancies.

There is no doubt that immunotherapy will play a big role in managing cancer moving forward, either as consolidation or, logically, in combination with chemotherapy, since damages induced by chemotherapy likely render cancer more immunogenic. This relatively new field of immunooncology is rapidly growing, taking advantage of other strategies, as well, from new monoclonal antibodies; to bispecific antibodies, such as blinatumomab and several others in the pipeline (aiming at rescuing the function of T cells or NK cells); and of course, cell therapies with CAR-T cells, the results of which were also updated at the meeting.

CAR T-cells so far have shown amazing activity in a number of B-cell malignancies, particularly in acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma, while other targets are being explored, including in solid tumors and myeloma. An intense race is on for armed modified T-cells, with no fewer than 17 companies currently involved just in CAR type T-cell therapies.

Besides being a core tool in immunotherapy, monoclonal antibodies also serve as drug carriers (ie, antibody-drug conjugates), several of which were updated at ASCO, both in solid tumors (eg, TDM-1 in breast cancer) and lymphoma.

Meanwhile, the field of small molecules or targeted therapies continues to grow, as well. For example, impressive results from the PALOMA-3 trial were presented for the CDK 4/6 inhibitor palbociclib in ER-positive metastatic breast cancer. The study was stopped early after an after interim analysis showed more than double disease control duration in the experimental arm, also providing an opportunity to delay chemotherapy in endocrine resistant metastatic breast cancer. Similarly, the HELIOS trial explored the integration of ibrutinib, the first-in-class BTK inhibitor, with chemotherapy (bendamustine/ rituximab plus ibrutinib or placebo) in relapsed/refractory CLL, showing an impressive 80% reduction in the risk of progression, with no significant added toxicity.

One of the other major focuses of cancer meetings these days is trying to take advantage of high throughput technologies to tackle the extraordinary diversity of cancer to help refine treatment decisions (ie, precision medicine). Besides the rapidly evolving and growing complexity of the numerous technologies and platforms explored, there is a similarly enormous and needed effort to cope with big data to try to create usable practical knowledge. This process should definitely focus on optimization of types and sequences of therapies to improve patient outcomes and hence, reduce costs along the way (reducing variance of management, redundancy, and wrong choices!).

As I introduced Jay Freireich as one of the winners of the third annual Giants of Cancer Care Awards, it seemed very appropriate to be acknowledging him in 2015, as he is the father of modern oncology (first chemotherapy regimen in ALL: VAMP), the discoverer of platelets transfusion, and made several other enduring contributions. Like when Jay started his career, we are definitively entering a new era in oncology, one in which we will not only start to shy away from chemotherapy in some diseases, but some of the emerging novel options—particularly immuno-oncology&mdash; will lead to improved outcomes that will not be measured in months, but in years...and hopefully, decades.

The ASCO annual meeting has retained its core purpose of providing a unique platform for oncologists to interact and exchange the latest practice-changing research.

ASCO 2015: Immuno-Oncology Again Takes Center Stage

When prostate cancer metastasizes, the propensity is for the disease to follow the drainage of the prostate through pelvic lymphatic channels. Unfortunately, the pelvic lymphatics on an individual basis are variable, and radiographic imaging and functional tests have yet to show significant sensitivity for detecting lymph node disease. As such, current surgical practice is to perform lymph node dissection (LND) in patients who are at higher risk of harboring disease in the lymph nodes.

The past decade has demonstrated a movement toward more extensive LND in order to sample and remove more lymph nodes. Studies have shown that a limited LND overlooks a large number of nodes, and the 

 and National Comprehensive Cancer Network guidelines suggest performing an extended LND if an LND is to be done at all. The enthusiasm for a more aggressive extended LND needs to be balanced against possible risks, in order to avoid harm to the patient. The number of lymph nodes removed has been used as a surrogate for LND quality, though the actual template followed is likely of more significance. Experienced surgeons are more likely to perform extended LND, as this involves delicate dissection around major pelvic blood vessels.

Recent regulatory recommendations have advocated against PSA screening to reduce overdiagnosis and overtreatment, and has been a topic of major debate. However, a product of reduction in the use of PSA screening may be a stage migration toward more patients presenting with locally advanced and/or metastatic disease. The main advantage of extended LND is in staging these patients. As lymph nodes can be positive in >30% of high-risk individuals, the earlier detection of patients with N+ disease can allow for administration of adjuvant therapies, better assessment of prognosis, and enhanced ability for patient counseling. The ability to accurately assess the lymph node status at the time of surgery is an advantage of surgery compared to radiation treatment.

Another benefit of extended LND is the removal of micrometastatic disease that may in turn impact survival. In other malignancies, LND has been shown to confer a survival advantage. Using another urologic pelvic malignancy as an example, in bladder cancer the evidence for a survival advantage with extended LND is stronger. The oncologic benefit of extended LND in prostate cancer is unproven; however, several retrospective studies have shown an advantage to biochemical recurrence-free survival and cancer- specific survival.

At City of Hope, the urologic oncology team has 5 years of experience in robot-assisted extended pelvic LND at the time of prostatectomy, having performed the procedure in over 1,000 patients. The technique has continued to progress and is proven to be safe. We’ve demonstrated in several publications that the lymph node yield is increased compared to limited LND (from 7 to 22), nodal disease detection is improved (from 4% to 12%), and patients do not experience more complications. We have cared for patients with early lymphatic spread of cancer that remain cancer- free for a prolonged period of time after extended LND and no further therapy. Current and future enhancements will focus on refining dissection mapping using novel fluorescent and antibody- labeled techniques. In this way, we aim to discover which patients would benefit most, which patients may be spared LND, and which patients need a deliberately more thorough LND.

Extended LND removes more cancerous lymph nodes and optimizes the staging ability of prostatectomy. Patients may have one treatment opportunity to have these lymph nodes removed, and surgical treatment at a center with expertise in this procedure can offer that chance.

The past decade has demonstrated a movement toward more extensive LND in order to sample and remove more lymph nodes.

Tracing the Path of Prostate Cancer Spread

Cancer is one of the leading causes of death in the United States, and is one of the most common, impairmentcausing, and costly diseases affecting Americans. The good news is that more people are surviving as a result of diagnostic and therapeutic advancements.

The cancer patient’s journey is an intense fight on two fronts: (1) overcoming and managing disease and,(2) coping with often debilitating and even disabling adverse effects and impairments. Cancer- and treatment-related impairments may include profound fatigue, chronic pain, decreased physical and cognitive function, as well as many others. Many times, impairments exist long after treatment. Few patients are prepared for the discouraging and devastating toll that is taken as a result of cancer and its treatment.

Survivors are commonly told to expect a “new normal” before having received rehabilitation services that may facilitate higher level functioning. The lack of comprehensive rehabilitation services is a profound source of unnecessary suffering for survivors. Evidence suggests that 65% to 90% of patients with cancer have functional impairments with fewer than 30% who actually get referred for rehabilitation services. Excluding inpatient consults, less than 2% of patients receive rehabilitation care.

Impairment-driven cancer rehabilitation can provide a solution by focusing on screening and treating physical and psychosocial impairments simultaneously and across the continuum of care. If patients with cancer are routinely screened for impairments and then appropriately referred to trained rehabilitation professionals, it is reported that patients will experience significant improvements in function, decreased disability, and increased health-related quality of life.

One model of cancer rehabilitation is the Survivorship Training and Rehabilitation program (STAR). The program provides a framework for the development of a multidisciplinary cancer rehab team. The STAR program incorporates training for clinicians, nurses, therapists, and support staff, and provides protocols to ensure the highest quality of cancer care. The model consists of the following: patient screening prior to undergoing acute cancer treatments, early identification of impairments, prehabilitation(if indicated), outcomes tracking, and treatment of functional deficits throughout the survivorship continuum.

Prehabilitation is a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment. It includes physical and psychological assessments that establish a baseline functional level, impairment identification, and interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments 

		Figure 2. Cancer Prehabilitation vs Usual Care and Education

Four outcomes should be monitored and include clinician education, patient function, patient satisfaction, and referrals/revenue to the institution.

Impairment driven cancer rehabilitation is a critical part of high-quality care. The American Cancer Society, Institute of Medicine, and the Commission on Cancer mandate that cancer rehabilitation and survivorship care must be a distinct and well-developed part of cancer treatment.

The need for access to rehab services is urgent and cannot be met by general wellness programs. Cancer patients need specialized medical rehabilitation services designed specifically for their unique needs. The goal of a cancer rehabilitation program is to help cancer survivors have the best possible life every day during and after cancer. Cancer rehabilitation has been proven to be cost effective and should be standard of care to reduce disability and maximize patients’ quality of life. As Dr Barry Brooks with the US Oncology Network states, “Cancer rehabilitation before, during, and after therapy is the largest unaddressed need in oncology. Routine referrals to cancer rehabilitation are not optional—they are absolutely essential to high quality care.”

			American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.

			Silver et al. Impairment-Driven Cancer Rehabilitation: CA: A Cancer Journal for Clinicians, Sept 2013,63:5.

			Cheville AL, Troxel AB, Basford JR, Kornblith AB. Prevalence and treatment patterns of physical impairments in patients with metastatic breast cancer. 

			Hansen DG, Larsen PV, Holm LV, et al. Association between unmet needs and quality of life of cancer patients: a population-based study. 

The lack of comprehensive rehabilitation services is a profound source of unnecessary suffering for survivors.

Impairment-Driven Cancer Rehabilitation Improves Survivors' Quality of Life

On the tail of AACR last month and ACSO coming up at the end of this month, the continued transformation happening in oncology reverberates more and more loudly. As I have reviewed several times in this column, the changes occurring in cancer are unprecedented and will have profound impact. This goes across the board, from novel therapies—small molecules targeting the BCR pathway, such as BTK or PI3K inhibitors (which are changing the field in CLL and likely in MCL), second- or third-generation EGFR inhibitors targeting resistant variants in lung cancer, and BRAF inhibitors in melanoma or hairy cell leukemia, just to name a few&mdash;to the amazing development of checkpoint inhibitors (melanoma, lung cancer, Hodgkin lymphoma) and the entire field of cell therapies with CAR-T cells and derivatives.

In many instances, these changes are so dramatic that physicians and patients want access to such compounds or technologies before they receive regulatory approval. Unfortunately, accessing these promising therapeutics can be difficult. Many of the sickest patients with refractory disease do not qualify for clinical trials. Furthermore, entire new paradigms can sometimes develop through the use of unapproved drugs, as illustrated by the thalidomide story in multiple myeloma, where it was first used off study, out of despair in a patient with refractory disease (based on its all-too-well-known antiangiogenesis effect, explaining deformations seen in newborns). The initial results were so impressive that it opened an entire new field with IMiDs in a variety of malignancies.

Mechanisms to gain access to nonapproved drugs exist through the expanded access programs, commonly referred to as “compassionate use.”

The process to make this happen is typically very complicated, involving both the sponsor and FDA, as well as local IRBs. In most cases, however, such requests are denied for a variety of reasons.

The complexity of the issues at stake resides in the multiple aspects involved, from ethical questions to regulators’ concerns over liabilities for allowing access to unapproved drugs. I believe an important step forward was recently made when Johnson & Johnson (J&J) announced its plans to create a Compassionate-Use Advisory Committee (Comp-AC) to streamline and organize this process.

The CompAC committee will consist of 12 members, including doctors, bioethicists and patient representatives. This committee will independently examine all requests submitted (online or through a toll-free hotline) in a timely manner and then render an opinion to J&J.

Although CompAC received positive coverage across the world, including on the frontpage of 

, some critics have emerged arguing that this will not truly help in practice. Concerns mentioned include how many cases will actually benefit (ie, “not everyone can benefit…”), what eligibility criteria will be used, and can a pharma-sponsored bioethics board fairly decide who receives experimental drugs? Others have suggested that before forming an independent, national advisory board, requests at-large for all experimental drugs that appear very beneficial in early trials should be reviewed.

Though compassionate use remains a complex societal issue, I applaud the initiative of J&J to at least offer a first step. If successful, CompAC will serve as a model for others in industry and government to follow in addressing this crucial issue of improving the process of expanded access.

I believe patients—who have been integral to the development of thousands of drugs over the years&mdash; deserve a dedicated, simplified process to help those who do not qualify for clinical trials. Additionally, we must also increasingly focus on biomarker-driven studies, which might offer options to patients who do not otherwise qualify for trials, frequently due to having received too many prior lines of therapy.

The mere fact that we are finally openly discussing this issue is progress in itself. This is also definitely the product of the tremendous advancement in oncology— the fact that we have had great success in developing novel agents has been game-changing and means that, logically, we as a society must now make the best effort to help patients with refractory disease benefit from this progress. It is a wonderful problem to have&mdash;let’s address it!

Dr. Andre Goy discusses efforts to improve "compassionate use" programs that expand access to promising drugs that are not yet approved by the FDA. 

June 2015 | Oncology & Biotech News

Late-Stage Studies Star at ASCO 2015

ASCO 2015: Immuno-Oncology Again Takes Center Stage

Tracing the Path of Prostate Cancer Spread

Impairment-Driven Cancer Rehabilitation Improves Survivors' Quality of Life

A Promising Move Toward Compassionate Access to Drugs