ASCO Backs Bone Drugs for Myeloma

Recommended for patients with or without evidence of lytic damage

Patients with symptomatic multiple myeloma should receive bone-modifying therapy irrespective of evidence of lytic destruction or spinal compression fracture, according to an updated guideline from the American Society of Clinical Oncology (ASCO).

Treatment options consist of the intravenous bisphosphonates pamidronate and zoledronic acid (Zometa) or, alternatively, the RANK ligand inhibitor denosumab (Xgeva). Denosumab might be preferred over zoledronic acid for patients with renal impairment, as the RANKL inhibitor has been associated with fewer renal adverse events.

 The primary purpose of the update, and associated expert-panel review, was to determine whether the 2007 recommendations remain valid. ASCO initially published clinical guidance about the use of bone-modifying agents in myeloma in 2002.

“These recommendations are consistent with the previous recommendations, with new information on denosumab,” the guideline authors stated. “Additional modifications were made to some of the recommendations on the basis of recent data to better clarify the indications for treatment, duration of treatment, and associated complications of treatment.”

The panel, chaired by Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, and Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, updated the ASCO recommendations after examining 35 relevant studies identified by means of a targeted systematic literature review. The review included randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies.

Key recommendations included:

  • Initiate bone-modifying therapy for patients with imaging-based evidence of lytic disease and for patients with osteopenia in the absence of lytic disease
  • Use bone-targeted agents as adjunctive therapy for controlling pain associated with osteolytic disease and for patients receiving other interventions for existing or impending fractures
  • Initiate intravenous bisphosphonates in patients with normal radiographs or osteopenia by bone mineral density measurements
  • Do not use bone-modifying agents in patients who have monoclonal gammopathy of undetermined significance, except when osteopenia exists
  • Reduce the dose of zoledronic acid in patients who have pre-existing mild or moderate renal impairment
  • Consider denosumab as an alternative to zoledronic acid for patients with compromised renal function
  • Use serum creatinine monitoring before each dose of a bisphosphonate, in accordance with FDA labeling
  • Perform intermittent evaluation of all bisphosphonate-treated patients for presence of albuminuria

The updated guideline also includes a table with the estimated cost of bone-modifying agents. Pamidronate and zoledronic acid had per-dose costs of $30.67 and $53.64, respectively, whereas each dose of denosumab cost $1,995.48. The estimated 1-year costs were $398.71 for pamidronate, $214.56 for zoledronic acid administered every 12 weeks, $697.37 for zoledronic acid every 4 weeks, and $25,9341.24 for denosumab every 4 weeks.

A compendium of ASCO recommendations related to bone-modifying therapy in myeloma is available on the organization’s website. The update was also published in the Journal of Clinical Oncology.

Early-Stage Lung Ca: Better OS with Surgery?

Lobectomy seems to offer better long-term outcomes over radiotherapy, yet the latter is still gaining ground

An ongoing debate in the lung cancer community is whether patients with early-stage disease benefit more from surgery or from stereotactic body radiation therapy (SBRT). Radiation oncologists are certainly on board with SBRT in inoperable patients, and there is some data to back up that assertion, as highlighted in this ASCO Reading Room articlefrom last year.

Meanwhile, thoracic surgeons seem to be moving away from lobectomy, and have stumped for less aggressive surgical approaches, such as wedge resection and segmentectomy.

But any discourse gets that much livelier when there’s someone who is willing to offer a third opinion. Researchers at two University of California branches took on that monkey-wrench role with their study in U.S. veterans that compared lobectomy with SBRT — and decided that surgery was the winner. In an interesting twist, the authors are affiliated with radiation oncology — and not surgery — departments at their respective institutions.

“Our data suggest that the more aggressively we treat early lung cancer, the better the outcome,” noted Alex Bryant, of the University of California, San Diego, in a statement. “This study is one of the best-powered and detailed analyses to date and suggests that lobectomy is still the preferred treatment of this disease for most patients.”

Surgery Scores

Bryant and his colleagues identified early-stage non-small cell lung cancer (NSCLC) patients from the VA Informatics and Computing Infrastructure (VINCI). He described VINCI as “an extremely rich source of health information” from which the authors were able to gather detailed data related to a large, nationwide group of veterans.

The study population ultimately consisted of a little over 4,000 patients (97% male) who were diagnosed with clinical T1 or T2a (<5 cm in greatest dimension), N0 (no regional lymph node metastasis), M0 (no distant metastasis), biopsy-proven NSCLC. The diagnoses took place between Jan. 1, 2006 and Dec. 31, 2015.

Patients were treated definitively with either surgery or radiation. Those with a history of prior malignancy, those with a missing cause of death, those treated more than 6 months after diagnosis, and those with missing covariates were excluded. Covariates derived from VINCI were tumor size, tumor grade, histology, patient age, sex, race, and tobacco history. Having these data makes the registry particularly unique, Bryant noted.

“Factors such as these are often not available and have not been consistently addressed in previous studies, which sets this study apart.”

In terms of the procedures themselves, SBRT was defined as the delivery of one to five daily fractions of radiation directed at the lung (mean biologically equivalent dose of 124 Gy10), while the surgical groups were divided into lobectomy and sublobar resection. The latter included wedge and segmental resection; video-assisted thoracoscopic surgery and open surgeries were combined for this analysis.

The authors compared cancer-specific survival among patients receiving lobectomy, sublobar resection, or SBRT with univariable and multivariable competing risk analyses.

The unadjusted analysis revealed higher immediate post-procedural mortality in the surgery groups versus the SBRT group. While multivariable analysis that looked at long-term survival found higher cancer-specific mortality for SBRT compared with lobectomy (subdistribution hazard ratio 1.45, 95% CI 1.09-1.94, P=0.01), there was no survival difference between SBRT and sublobar resection (subdistribution HR 1.25, 95% CI 0.93-1.68, P=0.15).

“Despite the higher postoperative mortality risk, the lobectomy group had the lowest unadjusted risk of all-cause mortality at 5 years,” the authors wrote. “In the lobectomy group, the unadjusted 5-year overall survival [OS] was 70%, followed by sublobar resection at 56% and SBRT at 44%.”

In addition, the multivariable Cox proportional hazards model showed that SBRT was tied to a 38% increased risk of all-cause mortality versus lobectomy (HR 1.38, 95% CI 1.08-1.78, P=0.01).

There was no significant difference in OS between the SBRT and sublobar groups (HR 1.17, 95% CI 0.90-1.53, P=0.85), and there were no significant differences between groups when evaluating noncancer mortality based on univariable or multivariable analysis. There also was no difference in OS or cancer-specific survival between patients who received wedge versus segmental resection (P>0.09 in all unadjusted and adjusted analyses).

Finally, the authors noted that for every 10 Gy increase in biologically equivalent radiation dose, the risk of cancer-related death decreased by 7% (subdistribution HR 0.93, 95% CI 0.86-1.00, P=0.06).

A Resolution?

In spite of the perioperative mortality risks linked with surgery, lobectomy improved survival compared with SBRT in the long term, the researchers concluded. So did the group make the ultimate mic drop in favor of lobectomy? Not quite.

As one MedPage Today reader commented, SBRT is generally reserved for patients who are poor candidates for surgery. But a number of trials designed to compare SBRT with surgery in early-stage disease — STARS, ROSEL, RTOG 1021 — were shuttered early because of poor accrual.

“The probable reason that earlier prospective randomized trials failed to accrue was because surgeons who had operable stage I patients would not consider SBRT, and patients who were not surgical candidates didn’t qualify for randomization in the failed studies,” the reader pointed out.

That leaves the lung cancer community anticipating results from two recently launched trials — VALOR and STABLE-MATES.

The JoLT-Ca Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) for Lung Cancer (STABLE-MATES) trial aims to recruit 258 patients at more than 30 institutions, and has an estimated primary completion date of December 2021.

STABLE-MATES’ principal investigator, Robert Timmerman, MD, of UT Southwestern Medical Center in Dallas, explained in a statement that the “two therapies [surgery and SABR] are both fiercely competitive, like thoroughbreds in a race. Yet when not competing on the track, they reside together in a stable enjoying each other’s company — ready and eager to be called on for the next challenge.”

Meanwhile, the currently recruiting Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR) trial will compare the two modalities in 670 patients at 16 VA centers. The estimated primary completion date is September 2027.

VALOR co-principal investigator Drew Moghanaki, MD, MPH, of the VCU Massey Cancer Center in Richmond, VA, noted in a statement: “There is a lot of research that suggests stereotactic radiotherapy might be just as effective as surgery for lung cancer, or even better. Currently, more than 90% of lung cancers that are caught at an early stage can be controlled with this non-surgical treatment. We know it is often safer than surgery and, for this reason, cancer researchers now question whether surgery is still the optimal treatment for lung cancer.”

He added, however, that while this new treatment approach is promising, there has as yet been no successful comparison of stereotactic radiotherapy with surgery in a head-to-head trial to know how well it works in the long-term: “There are many oncologists who believe stereotactic radiotherapy might be the best way to treat lung cancer. But, until a study like the VALOR trial is completed we will not know what is the best treatment for all of our lung cancer patients.”

More on Surgery

Other recent research has also evaluated ways to refine lung cancer surgery:

  • Two investigators at Houston Methodist Hospital reported on the “five on a dice” port placement and technique to allow for minimal assistance during lobectomy
  • An Italian team explained why the technique for video-assisted thoracoscopic surgery (VATS) lymphadenectomy was the same as that of thoracotomy in early-stage lung cancer
  • Another group of Italian researchers found that VATS lobectomy for locally advanced-stage NSCLC was safe and effective in appropriately selected patients, ensuring perioperative results similar to those obtained in early-stage tumors
  • Japanese researchers reported on two patients in whom salvage VATS lobectomy was feasible after SBRT

The study by Bryant’s group was supported by the National Institutes of Health. Bryant disclosed no relevant relationships with industry; one co-author disclosed support from EMD Serano.

The VALOR trial is funded by the Veterans Affairs Cooperative Studies Program.

CAD: Striving for Better Lung Ca Imaging Reports

Swiss researchers aim to make radiology reports more meaningful by extracting TNM staging data

Computer-aided detection (CAD) has made its mark in the cancer field, most notably for breast cancer detection. In lung cancer, the use of CAD systems can improve the performance of radiologists in pinpointing pulmonary nodules. But CAD systems in lung cancer have suffered from some shortcomings, such as only little to modest improvement in sensitivity, an increase in false positives, and issues with the level of automation as well as the ability to detect different types and shapes of nodules.

Another potential pitfall: How can CAD results, which are rendered in the language of radiologists, be matched with the language of oncologists?

Bram Stieltjes, MD, PhD, of the University Hospital Basel in Switzerland, and colleagues sought to answer that question by developing an in-house CAD image-processing software for PET/CT lung studies. The goal with a study they presented at the 2017 Radiological Society of North America (RSNA) meeting in Chicago was to decrease tumor, node, distant metastasis (TNM) misstaging, and subsequent erroneous treatment planning for lung cancer patients.

Stieltjes spoke with ASCO Reading Room about the impetus for this research, and the plans for launching the CAD program at his institution as soon as early 2018.

Study Details

The group evaluated reports from the radiology information system (RIS) of 145 non-small cell lung cancer (NSCLC) patients who underwent a primary staging FDG-PET/CT exam at the facility. TNM (edition 7) was determined according to the text information in the reports by a radiologist and a nuclear medicine physician.

The team then downloaded the corresponding PET and CT image data sets from the university’s picture archiving and communication system (PACS). These data sets were transferred to 3D-slicer-based prototype software. As the authors explained, the image-processing application allows for manual segmentation of tumors, lymph nodes, and metastasis using a set of labels including location information and morphological TNM features.

Stieltjes et al reported that in a substantial number of patients, not enough information was provided by the original report to extract a distinct TNM stage:

  • T: 18.6% (27/145)
  • N: 10.3% (15/145)
  • M: 2.1% (3/145)

“Furthermore, in 29 cases, there was a considerable discrepancy between the report and annotation: upstaging due to the annotations: T: n=11, N: n=6, M: n=4; downstaging due to the annotations: T: n=3; N: n=4; M: n=1.”

Applying the image-processing tool and using a segmentation-based approach to the image data sets allowed the team to extract TNM information in all patients, the researchers explained, adding that their approach with tumor labels allows for a clear definition of cancerous lesions in a standardized and reproducible manner.

“We could demonstrate that the proper TNM stage could not be derived from unstructured PET/CT reports in a roughly 30% of the cases. This commonly affects the T-stage because of missing diameter measurements, but also the N and M stage.”

The investigators concluded that the labels generated using this image-processing tool could be directly translated into clinical decision-making, such as tumor boards, and were less prone to interpretation.

The following interview with Stieltjes, who is the head of research coordination for radiologist and nuclear medicine at the Basel institution, has been edited for length and clarity.

Why did your group decide to undertake this study?

Stieltjes: We were trying to standardize our output, and perhaps implement the much-hyped machine learning — what some might call a type of artificial intelligence inroutine clinical practice. I’ve been [at Basel] about 3 years, and our first year we looked for projects that might be suitable to achieve this goal. Lung tumor staging was one such project where the data was there, and there was a substantial number of patients.

The clinical work time that is done on preparing a lung PET/CT report is very high; we [radiologists] take about an hour per report. So there is much that can be gained in terms of efficiency. My gut feeling was that … even when we put in the work on interpretation and reporting, we don’t always deliver the information that is necessary for the oncologists.

There’s an ongoing conversation in radiology about the usefulness of structured reporting versus the free-text reporting described in your study. Do you see structured reporting being of some benefit along with the image-processing tool used in your research?

Stieltjes: Structured reporting does not touch on the radiological workflow as it is right now; it is only formalizing the way text is inputted. Radiology is still interpreting the image and generating a report. However the link between the text and the image is very weak.

What we are presenting is a sort of third way: You first define all the important anatomical features in a structured way with labels. Then the job of the radiologist is not scrolling and talking, but scrolling and clicking, labeling — to place a label on an image in the study series. This then goes to a database.

As a recipient of the report, I can learn and understand what the radiologist sees; I’m able to have a direct link between his or her knowledge and the actual place in the image where their skills have seen an area of importance.

Is the system described in the study ready for clinical deployment?

Stieltjes: We’re on the brink of putting the annotation portion for lung tumors into clinical routine — not the decision-making part. What we’re trying to do is change the radiologist workflow, so that they’re labeling as part of their report — so we focused on getting the annotation part done first. We hope to have it into practice in the early part of 2018.

The next part is the capability to detect all lung lesions, which the radiologist will review, and we’re confident that we’ll have that in the next generation of the application.

What feedback have you received from oncologists and other clinical colleagues about this system?

Stieltjes: This project has been conducted in partnership with our oncology department. The oncologists are really looking forward to having all the TNM information in our reports for two reasons: One, TNM information was not always included in reports; and two, images were not always included in reports. Now labeled images and TNM stage will be part of every report.

Of course, oncologists want to have pathology for correlation, so our TNM stage will be provisional until they get a pathological confirmation.

ASCO: Tumor ‘Sidedness’ Affects Survival

New analysis of colon cancer trial could aid treatment decisions.

The “sidedness” of a primary colon cancer should play a part in treatment decisions for patients whose disease has spread and especially in what targeted agent to use, a researcher said.

In a new analysis of a Phase III trial, patients whose tumors originated on the left side of the colon did better than those with right-sided primary tumors, according to Alan Venook, MD, of the University of California San Francisco.

Importantly, the choice of which targeted agent was added to standard chemotherapy played a “surprising” role in treatment outcomes, Venook told reporters in a briefing in advance of the annual meeting of the American Society of Clinical Oncology (ASCO), starting here June 3.

Venook said the investigators thought before they undertook their analysis that the sidedness of the primary tumor “was not likely to make a big difference.”

But in one arm of the reanalysis, the combination of cetuximab (Erbitux) and chemotherapy resulted in almost a 20-month difference in overall survival.

“This was a dramatic finding,” Venook said.

He said he and colleagues are now conducting molecular studies in the hope of teasing out what underlies the sidedness difference, but in the meantime patients with right- and left-sided tumors “should be treated differently.”

The analysis is based on the large CALGB/SWOG 80405 trial, which looked at outcomes in patients given standard chemotherapy for metastatic colon cancer with the addition of either cetuximab or bevacizumab (Avastin).

Both drugs are approved to treat metastatic colon cancer but they had not previously been compared head to head, commented Richard Schilsky, MD, a former president of ASCO and currently the society’s chief medical officer.

Cetuximab targets the epidermal growth factor receptor (EGFR) while bevacizumab inhibits the vascular endothelial growth factor (VEGF), Schilsky, who is also a study co-author, told MedPage Today earlier.

In the original trial, presented 2 years ago at the ASCO General meeting, neither combination showed a survival advantage over the other, Venook said.

But some small studies have hinted that the sidedness of the primary tumor might affect treatment outcomes, he said. As well, the two sides of the colon arise from different parts of the embryo, so it “would not be surprising” to find that they react differently to treatment.

To investigate the issue, he and colleagues reanalyzed the data by sidedness and treatment combination.

Overall, they found, the median overall survival among the 732 patients with a left-sided tumor was 33.3 months, compared with 19.4 months among those with a right-sided tumor. The difference yielded a hazard ratio for survival of 1.60, with a 95% CI from 1.37 to 1.86, which is significant at P<0.001.

The difference was narrower among patients treated with bevacizumab — 31.4 months among the 356 patients with a left-sided tumor and 24.2 months among those with a right-sided lesion. The 1.297 hazard ratio (95% CI 1.05 to 1.60) was significant at P=0.017.

But it was dramatically better among those treated with cetuximab, Venook said. Those with a left-sided tumor had a median survival of 36 months, compared with 16.7 months for those with a right-sided cancer. The hazard ratio was 1.987 (95% CI 1.60 to 2.46) and was significant at P<0.001.

Venook said sidedness is almost certainly a “surrogate marker” of something more precise and added that he and colleagues are hoping that the molecular analysis will lead to “crisp biological testing.”

But until then, “the sidedness can help us make decisions, in the context of all the other information we gather,” he said.

The report is an illustration of “how very large federally funded studies, such as this one, can really help us to differentiate some of the issues we need to understand to treat our patients,” commented ASCO President Julie Vose, MD, of the University of Nebraska Medical Center in Omaha.

Vose said the study is “definitely going to help us generate hypotheses for future studies.”

ASCO names immunotherapy as cancer advance of the year

With the start of another year, the American Society of Clinical Oncology (ASCO) has announced the cancer advance of the year as the developments seen in immunotherapies.

Worldwide, there will be an estimated 22.2 million new cancer diagnoses by 2030, with a disproportionate number of cancer deaths in Central and Southeast Asia. [Stewart BW, Wild CP, World Cancer Report 2014] Despite the growing challenges to cancer care, breakthroughs in the development of immunotherapies demonstrate the continued efforts to improving patients’ lives.

“No recent cancer advance has been more transformative than immunotherapy. These new therapies are not only transforming patients’ lives, they are also opening intriguing avenues for further research,” said ASCO President Julie M. Vose. “Advances like these require bold ideas, dedication and investment in research. If we are to conquer cancer, we need to invest more as a nation to support a strong biomedical research enterprise.”

The call for immunotherapies as the advance of the year highlights the continued progresses with the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab. These drugs targeting CTLA-4 and the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) proteins involved in the regulation of cell apoptosis have shown efficacy in advanced melanoma, extending patient survival from months to years with manageable adverse effects.
The past year saw evidence of PD-1/PD-L1 blockade in particular as an effective strategy in lung cancer as well. (See MIMS Onocology, “Pembrolizumab improves survival in PD-L1-positive advanced NSCLC patients“) This has led to the US FDA approvals of Bristol-Myers Squibb’s nivolumab and Merck Sharp & Dohme’s pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC) after failure of previous treatment.

Other immunotherapies in development include Roche’s atezolizumab, a PD-L1 inhibitor, which has received US FDA breakthrough designation for PD-L1-positive NSCLC and has shown additional success in a phase II study on advanced bladder cancer.

Ongoing studies looking at PD-1/PD-L1 inhibitors in kidney, liver, and head and neck cancers, and exciting evidence pointing to their potential in haematological malignancies (acute lymphoblastic leukaemia, diffuse large  B-cell lymphoma, Hodgkin’s lymphoma) and glioblastoma suggest that progress will continue to be seen in this area of research. Clinical trials evaluating combination strategies with immunotherapies are also underway.

In addition to the advances in immunotherapy, ASCO has highlighted the advances in precision medicine and cancer prevention for improving patient care and quality of life. As knowledge of tumour biology continues to grow, powerful new treatments that block specific molecules (eg, olaparib targeting PARP and palbociclib targeting cyclin-dependent kinases 4 and 6) or target genetic alterations (eg, KRAS-, EGFR- and ALK-targeted therapies) that fuel cancer growth are becoming standards of care for many cancers. These targeted approaches have also shown promise in some difficult-to-treat cancers of blood, ovaries, breast and kidneys.

Between October 2014 and October 2015, the US FDA approved 10 new cancer treatments, expanded the use of 12 previously approved cancer therapies and one device, and approved one new vaccine for the prevention of cervical and other cancers.

As Vose emphasized, a critical component in the successes in cancer care is the availability of resources. “If we are to conquer cancer, we need to invest more as a nation so that we can prepare for what lies ahead,” she wrote. “Cancer care is set to change more dramatically in the next 20 years than it did in the last 50 years, thanks in part to advances in health information technology and a deeper understanding of cancer’s molecular drivers. As biomedical discovery expands, we need to be able to answer difficult questions and pursue new research directions.”

These new research directions include exploring new ways to improve patient outcomes by combining different immunotherapies, combining immunotherapies with traditional treatments such as chemotherapy, radiation therapy and surgery, and starting immunotherapy earlier in the course of disease. Researchers are also looking to identify biomarkers that can predict response to immunotherapy and guide treatment decisions.

“In the near future, cancer immunotherapy may become the fourth pillar of cancer treatment, along with chemotherapy, surgery and radiation therapy,” the report’s authors wrote.

New ASCO Guidelines for Treatment of Stage IV NSCLC.

The American Society for Clinical Oncology (ASCO) has issued a new guideline for the treatment of stage IV non-small cell lung cancer. The new guidelines call for the use of 2 new monoclonal antibodies in patients whose disease has progressed after treatment with a platinum-based therapy.

ASCO has issued a new “Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer Guideline.” The new guidance calls for the use of two new monoclonal antibodies in patients with non-small cell lung cancer (NSCLC) whose disease has progressed after treatment with a platinum-based chemotherapy.

The new guidance was developed in order to answer the following question: “What systemic therapy treatment options should be offered to patients with stage IV NSCLC, depending on the subtype of the patient’s cancer?”

The ASCO committee conducted a systematic review of the literature and developed a “clinical practice guideline update targeted at health care providers (including medical oncologists, nurses, social workers, and any other relevant members of comprehensive multidisciplinary cancer care teams), and patients and their caregivers in North America and beyond.”

A Major Shift

ASCO issued a Special Announcement on October 19, 2015:

The U.S. FDA approved a monoclonal antibody agent for patients with NSCLC non-squamous histologies with progression on or after platinum-based chemotherapy on October 9, 2015, expanding upon the FDA’s previous approval for patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy on March 4, 2015. The FDA also approved a second monoclonal antibody for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy on October 2, 2015. ASCO guidelines are updated on a regular basis and the data accompanying these approvals will be examined during the next guideline update.

Other agents have also been approved for patients whose tumor has grown during or following treatment with platinum-based chemotherapy.

The More Things Change …

These new guidelines give clinicians more freedom in how patients are treated, and which patients receive treatment. The guidelines stress that “Decisions on chemotherapy should not be made on the basis of age alone. They also reiterate that “there is no cure for patients with stage IV NSCLC.”

Given that there is no cure, the guidelines can help clinicians extend both the lifespan of patients with stage IV disease as well as their healthspan.

Read the full reeport. URL:

Sunitinib Maintenance After Chemotherapy Improves Progression-Free Survival for Extensive-Stage Small Cell Lung Cancer.

After standard chemotherapy, maintenance therapy with sunitinib delayed relapse by approximately 1.5 months compared with placebo for patients with extensive-stage small cell lung cancer (SCLC), according to new findings from a phase II trial.

Dr. Neil Ready, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, presented results from the randomized, phase II Cancer and Leukemia Group B (CALGB) 30504 trial (Ready N et al., 2013) at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.

Sunitinib is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor that shows potent and selective activity against vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and other molecular targets implicated in tumor growth and angiogenesis. Sunitinib is currently approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. Although sunitinib and other RTK inhibitors have been studied extensively in non-small cell lung cancer (NSCLC) (Gridelli C et al.), few studies have examined sunitinib in SCLC.

CALGB 30504 Study Design

The CALGB 30504 trial began in 2007 as a phase I trial of concurrent therapy with sunitinib and standard chemotherapy in untreated extensive-stage SCLC. The concurrent regimen was not feasible, however, due to the risk of grade 5 neutropenia (Ready N et al., 2010). In 2008, the CALGB 30504 protocol was amended to a randomized phase II trial designed to evaluate maintenance sunitinib following chemotherapy. In the current analysis, 85 patients received 4-6 cycles of standard-dose chemotherapy with cisplatin/etoposide or carboplatin/etoposide every 21 days. Patients were randomly assigned to maintenance therapy with sunitinib 37.5 mg/day (n = 44) or placebo (n = 41) until disease progression. Crossover to sunitinib maintenance was permitted in the placebo arm at disease progression.

The median patient age was 60 years (range, 39-77 years). The majority of patients (76.5%) completed 6 cycles of chemotherapy; 26% received cisplatin and 74% received carboplatin. Among patients with a complete or partial response (n = 78), 34 patients (44%) received prophylactic cranial irradiation 4 to 6 weeks after completing chemotherapy.

Patients completed a median of two cycles of maintenance therapy (range, one to 17 cycles). In the sunitinib arm, 68% of patients completed 1 to 4 cycles, while 23% completed 5 to 8 cycles. Four patients (9%) completed 9 or more cycles of sunitinib maintenance. The crossover rate was high, with 40% of patients in the placebo group initiating sunitinib following disease progression.

Improved Progression-Free Survival

The CALGB 30504 trial met its primary endpoint of improved progression-free survival after chemotherapy with maintenance sunitinib. The median progression-free survival was 3.77 months in the sunitinib maintenance group, compared with 2.30 months in the placebo group (HR, 1.53; P = 0.037).

Despite the high crossover rate, maintenance sunitinib showed a trend toward improved overall survival compared with placebo. The median overall survival was 8.95 months in the sunitinib group and 6.89 months in the placebo arm (HR, 1.17; P = 0.27).

Evidence of Single-Agent Activity

An analysis of tumor size before and after crossover to sunitinib in six patients with disease progression in the placebo group also demonstrated the single-agent antitumor activity of sunitinib. In the 6 to 12 weeks prior to crossover, the tumors were exhibiting rapid growth. Following crossover to sunitinib, tumor growth slowed in each case, and some tumors decreased in size.

In another case, the pattern of tumor response during chemotherapy and maintenance provided additional support for single-agent activity with sunitinib. The patient showed a partial response to chemotherapy, which plateaued between cycles 4 and 6, but converted to a complete response during sunitinib maintenance. The complete response was maintained without progression for 15 cycles (45 weeks) of maintenance therapy.

Safety Findings

Maintenance sunitinib appeared safe and feasible at this dose. During maintenance, 46.5% of patients in the sunitinib group reported at least 1 grade 3/4 adverse event, compared with 19.5% of patients in the placebo group. The most common grade 3/4 adverse events during sunitinib maintenance were fatigue (19%), neutropenia (14%), leukopenia (7%), thrombocytopenia (7%), and hyponatremia (5%). Grade 4 events included gastrointestinal hemorrhage (n = 1) and pancreatitis (n = 1).

Next Steps

A biomarker analysis of blood samples is being planned, with the goal of identifying prognostic and predictive markers that may guide the selection of patients for maintenance therapy. A randomized phase III trial is being proposed to test the hypothesis that maintenance sunitinib after standard chemotherapy improves survival in patients with extensive-stage SCLC.

Dr. Ready explained the rationale for additional studies of maintenance sunitinib. “We felt that the [phase II] results were consistent with the hypothesis that there could be a 2-month or more improvement in overall survival with maintenance sunitinib in this setting. We feel that it is reasonable to consider a phase III trial to test that hypothesis,” Dr. Ready said.

Source: The oncologist


Current and Future Options for Targeting Activated Kinases in Acute and Chronic Leukemias

Contributors: Anna Azvolinsky, PhD, Anne Jacobson, MPH, CCMEP, CMPP

Tyrosine kinase oncogenes such as BCR-ABL and FLT3 are commonly mutated and activated in acute and chronic myeloid leukemias. The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myelogenous leukemia (CML) and provided new treatment options for patients with chronic myeloproliferative neoplasms and acute leukemias. In a special session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on the role of targeted therapy in acute and chronic leukemias, experts discussed the current clinical issues and future opportunities associated with the targeted inhibition of aberrant signaling pathways that drive the development and progression of these malignancies.

Chronic Myelogenous Leukemia

Resistance to BCR-ABL-targeted therapy in patients with CML arises through an array of potential mechanisms, ranging from non-specific multidrug resistance to inherent BCR-ABL genetic alterations. Michael J. Mauro, MDof the Knight Cancer Institute, Oregon Health & Science University, in Portland, Oregon, discussed targeted approaches to managing treatment resistance in patients with CML.

In 2001, the approval of imatinib, the BCR-ABL kinase inhibitor, launched a new area of targeted therapy for CML. Imatinib has been so successful that it has grown to become the targeted therapy all other therapies want to emulate—oncologists often aspire to finding the “imatinib” of other cancer types. As of 2013, five targeted agents are currently available for CML, including two agents, bosutinib and ponatinib, that joined the salvage treatment armamentarium in 2012.

After more than a decade of experience with imatinib in CML, the oncology community has gained critical insight about the development and progression of treatment resistance, with potential implications for other targeted therapies. Importantly, resistance to imatinib is a function both of time and disease volume. Early reduction of disease burden is associated with the reduction or elimination of unstable clones, leading to a reduction in the risk of relapse. Timely cytogenetic and molecular response is a strong predictor of functional cure, which is defined as the absence of meaningful proliferation even after treatment is stopped.

Options for patients who show early resistance to imatinib (e.g., BCR-ABL/ABL >10% at 3 months) include switching to another tyrosine kinase inhibitor based on mutational analysis, evaluating candidacy for stem cell transplant, or referring the patient to a clinical trial. Ongoing trials will evaluate the utility of various approaches to early resistance, including immediate versus delayed switch to an alternate targeted regimen. Treatment selection is further individualized based on a tolerability profile and likelihood of treatment adherence. Among current options, nilotinib, dasatinib, and bosutinib are proven salvage options with promising activity in the front-line setting. Ponatinib also represents a compelling salvage option, particularly for patients with heavily pretreated CML who have stopped responding to all other therapies. A phase III trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML is currently underway.

Chronic Myeloproliferative Neoplasms

Targeted therapy is rapidly changing the treatment landscape for chronic myeloproliferative neoplasms, including primary myelofıbrosis (MF), essential thrombocytopenia (ET), and polycythemia vera (PV). Following the identification of the JAK2V617F mutation in 2005, the first JAK1/2-targeted therapy was approved just six years later, in 2011. Claire Harrison, DM of the NHS Foundation Trust in the UK, discussed the current standard of care for primary MF, post-ET/PV MF, and other myeloproliferative neoplasms in the era of JAK1/2 inhibitor therapy.

Ruxolitinib was the first oral, selective JAK1/2 inhibitor approved for the treatment of intermediate- and high-risk MF, based on substantial reduction in spleen size and improvements in other constitutional symptoms and quality of life in the phase III COMFORT-1 and COMFORT-2 trials. To date, treatment with ruxolitinib has not resulted in any molecular remissions, although there is hope for the concept of a ‘cure’ with targeted therapy alone. In current practice, allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with MF. Other limitations of current systemic treatment options in MF include concerns about the induction of leukemia as well as the inability to reduce late myeloid transformation.

Building on the success of ruxolitinib, other JAK-targeted inhibitors in development include SAR302503, a selective JAK2 inhibitor; pacritinib, an oral, once-daily, highly selective inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3); and CYT387, an oral JAK1/2 inhibitor. Future clinical trials in this setting may focus on regimens designed to improve the hematologic toxicity profile of current JAK1/2 inhibitor therapy or improve treatment efficacy via the use of novel JAK1/2 inhibitors alone or in combination with other targeted agents, such as histone deacetylase (HDAC), phosphatidylinositol 3 (PI3)-kinase, and smoothened pathway inhibitors.

Acute Leukemia

Advances in the molecular profiling of acute leukemia, particularly the role of activating mutations that result in signaling molecule alterations, may introduce new opportunities for targeted therapy. Neil Shah, MD, PhD of the University of California, San Francisco, discussed the evolving rationale for kinase inhibition in the treatment of acute leukemia.

Acute leukemia is frequently associated with activating mutations in signaling molecules. Kinase inhibitors provide an effective, well-tolerated tool to substantially reduce the burden of disease and, when combined with chemotherapy, improve cure rates in patients with acute myeloid leukemia (AML). The number of possible combination regimens with other targeted agents is growing as novel pathway inhibitors are being developed. Performing detailed molecular analyses of tumor samples is becoming more feasible, and promises to facilitate the personalized selection of rational targeted therapies and combination regimens in the near future.

Several kinase inhibitors are in development for AML, but early stage results lag behind the advances seen in the CML setting. Many of the targeted multikinase inhibitors currently under development in AML may have a role as bridge therapy, providing patients the time to transition to a potentially curative stem cell transplant.

The key obstacle in the development of targeted agents for AML is a lack of a known dominant driver mutation. The most common mutation appears to be a tandem repeats of the activating mutations of the FLT3 receptor tyrosine kinase in about a quarter of patients. Agents such as quizartinib and crenolanib are in clinical trials, but rapid relapse is common. “FLT3 may be a passenger rather than a driver mutation [in AML] and not worth targeting,” saidDr. Shah. Inhibitors of KIT, JAK2, mTOR, and MEK are also under evaluation in AML, but their potential antitumor activity in patients who do not harbor mutated kinases is unknown.

Incorporating next-generation molecular sequencing tools into studies of targeted therapeutics will advance the use of personalized treatment in acute leukemia. Continued participation of patients with AML and other malignancies in clinical trials is strongly encouraged, Dr. Shah said.

Source: The oncologist