By Gena Cook, CEO, Navigating Cancer
2016 promises to be a transformative year for cancer care delivery, with the roll out of the Oncology Care Model (OCM). In a few short months, the Center for Medicare and Medicaid Innovation (CMMI) is expected to announce the 100 participants from the pool of OCM applicants that were submitted last June.
What do cancer centers need to understand about OCM now?
OCM is a payment reform model designed to improve episodes of care for patients undergoing chemotherapy. The goal of this payment model is to promote care delivery at the lowest cost, in the most medically-appropriate setting. An OCM episode of care begins with the initiation of chemotherapy treatment and extends over the following six-month period, but one beneficiary may undergo multiple OCM episodes of care during the five-year OCM performance period. Provider participants will consist of physician group practices, as well as practitioners in solo practice. One key feature of OCM is that it places the medical oncologist in the lead role of managing care quality, delivery and cost. In exchange, providers will earn a management fee of $160 per beneficiary per month. That’s $960 per 6-month episode.
In addition, practices will have the potential of earning an average of 12% shared savings through semi-annual performance-based payments – a figure which could amount to $16,000 per beneficiary per year.
Both of these OCM payments are in addition to practices continuing to bill traditional Medicare fee-for-service claims, including reimbursement for Part B drugs administered during OCM episodes at ASP plus a 4% to 6% margin.
While some of the OCM rules and specifications will remain vague pending the official start, here are five over-arching trends we can begin to consider now:
Putting these features in place now won’t just set practices up for success in advance of the inflection point in cancer care delivery that OCM will bring; they will improve experiences, and outcomes, for cancer patients. And that, ultimately, is the point.
By: Arnold DuBell, Ph.D., M.B.A., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
It seems impossible to attend an oncology conference these days without immuno-oncology being a significant focus, and it’s starting to become passé. Well, not quite. Two years ago the idea of this treatment class playing a role in gastrointestinal (GI) cancers seemed unlikely. However, as we learned yesterday at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium, these tumors might be immune-sensitive after all. Updated data and new results were reported for several checkpoint inhibitors, which collectively support the continued development of these drugs in GI cancers.
In gastric cancer, first results of the CheckMate-032 trial were presented for Opdivo® (nivolumab, Bristol-Myers Squib/Ono Pharmaceuticals).1 In a heavily pretreated population of 59 patients with gastric or gastroesophageal junction (GEJ) cancer, single-agent Opdivo (at a dose of 3 mg/kg) resulted in a 14% objective response rate (ORR), which included one patient with a complete response. Among the responding patients, median duration of response was 7.1 months. Across all patients, the median progression-free survival (PFS) was 1.4 months, the median overall survival (OS) was 5.0 months, the six-month OS rate was 49%, and encouragingly 36% of patients were alive at one year. There was a slight correlation between ORR and PD-L1 expression, with higher ORR observed in PD-L1-positive patients compared with PD-L1–negative patients (27% versus 12%, using expression in 1% or more of the tumor cells as the definition of PD-L1-positivity). Consistent with studies in other tumor types, Opdivo was well tolerated, with only 17% of patients experiencing a Grade 3 or 4 adverse event. The efficacy data for Opdivo appear, at first glance, to be in line with the activity previously reported for Keytruda® (pembrolizumab, Merck & Co.): 22% ORR, 1.9-month median PFS, and 69% six-month OS in heavily pretreated PD-L1-positive gastric cancer.2
Also debuting data in gastric/GEJ cancer at ASCO GI 2016 was avelumab (MSB0010718C, Merck KGaA/Pfizer). The gastric cancer cohort of the JAVELIN Solid Tumor trial enrolled 75 patients and treated them with avelumab monotherapy in either the second-line setting (n=20) or as maintenance therapy following first-line chemotherapy (n=55).3 In second-line, avelumab produced a 15% ORR and 2.7-month PFS among all patients, and like the Opdivo results there was a suggested correlation between ORR and PD-L1 expression, with higher ORR observed in PD-L1-positive patients compared with PD-L1–negative patients (20% versus 0%, using 1% or more as the definition of PD-L1 positivity along with caution due to small sample sizes). Similar outcomes were reported in the JAVELIN Solid Tumor Japan trial’s gastric cancer cohort: 15% ORR in all patients and suggested correlation with PD-L1 expression (40% in PD-L1-positive versus 7% in PD-L1-negative patients, using 1% or more as the definition of PD-L1 positivity and caution due to small sample sizes).4
Although these study data are all preliminary, they serve collectively to provide evidence that checkpoint inhibition has clinical activity in metastatic gastric cancer and support the multiple Phase III trials that are already underway for all three of these drugs. While these data also suggest PD-L1 overexpression might correlate with improved ORR, the data are reminiscent of outcomes observed in other tumors and further perpetuate ideas that PD-L1 might not be the best biomarker to select patients for treatment with a checkpoint inhibitor.
Results were also reported for this class in metastatic esophageal cancer. The Ono Pharmaceuticals-sponsored Phase II ONO‐4538‐07 study enrolled 65 squamous cell carcinoma esophageal cancer patients and treated them with single-agent Opdivo (3 mg/kg q2w). In this heavily pretreated population, Opdivo produced a 17% ORR by central review, with 1.5-month median PFS and 10.8-month median OS.5 Among those patients who achieved a response, the duration is quite long (median was not reached, but all responding patients seemed to remain in response for at least eight months based on a review of the spider plot). This trial did not provide an analysis of outcomes according to patient PD-L1 status or other biomarker.
The KEYNOTE-028 trial evaluated Keytruda (10 mg/kg q2w) in relapsed/refractory metastatic esophageal cancer patients, specifically enrolling only PD-L1-positive patients, defined as expression in 1% or more of tumor or inflammatory cells or positive bands in the stroma. In patients with predominantly squamous cell carcinoma treated in the third-line or later, the observed ORR of 30% among evaluable patients (n=23) was quite encouraging.6 These efficacy data were a reprisal of data originally presented at ASCO 2015,7 but of particular interest was new data presented on a gene expression signature composed of six genes that play a role in adaptive immune response. In tumors with a high inflamed signature score, there was a propensity toward higher likelihood of prolonged PFS compared with patients with a low score. Even among patients with a high signature score, there still appeared to be a subpopulation with greater benefit, so more work is needed to fully understand how to identify the most responsive patients with PD-1 inhibition, but this data was an intriguing step in the move beyond PD-L1 immunohistochemistry assays.
As in gastric cancer, development of PD-1 inhibitors is advancing quickly in esophageal cancer. Opdivo and Keytruda have recently initiated Phase III trials in this disease, with both targeting the relapsed/refractory setting.
The data for checkpoint inhibitors as reported at ASCO GI 2016 is focused within gastric, GEJ and esophageal cancers. However, previously reported data for Keytruda in colorectal cancer (CRC) was discussed, especially within the context of patient selection for use of checkpoint inhibitors. As reported originally at ASCO 2015, CRC and other GI tumors with high microsatellite instability (MSI-H) or that are deficient in mismatch repair (dMMR) have demonstrated high ORR and prolonged PFS when treated with Keytruda.8 Confirmation of this activity is ongoing in Phase II and Phase III studies. Clinical trials are also currently ongoing with Keytruda and Opdivo in pancreatic cancer and hepatocellular carcinoma. Although we won’t see clinical data in these indications at ASCO GI 2016, today’s Keynote address by Dr. Robert Vonderheide presented intriguing in vitro and in vivo data that supports pursuit of immunotherapy in pancreatic cancer through a combination approach of immune response activation (using chemotherapy, radiotherapy, and/or vaccination) and immune response maintenance (using checkpoint inhibition).9 For now, checkpoint inhibitors continue to garner significant attention across a range of cancer indications, and gastrointestinal cancers can no longer be considered immuno-insensitive.
The 2016 Gastrointestinal Cancers Symposium, being held January 21-23 in San Francisco, will attract cancer researchers and clinicians from around the world to hear the latest in colorectal, pancreatic, liver, esophageal, gastric and other GI malignancies. Three studies were previewed ahead of the meeting in a presscast.
Two support new treatments for neuroendocrine tumors (NETs) of the GI tract. NETs are a group of cancers that originate in hormone-producing (ie, neuroendocrine) cells of various organs in the body, with 60% being gastrointestinal. While they are diagnosed in the US each year in only about 8,000 people, their incidence is increasing and there are few treatment options after patients progress on somatostatin analogs (SSAs), according to presscast moderator and ASCO Spokesperson Smitha Krishnamurthi MD, of Seidman Cancer Center and the Case Comprehensive Cancer Center in Cleveland, Ohio.
Results of a third study suggest that preoperative treatment of locally advanced rectal cancer can be delivered more conveniently.
Everolimus Effective in NETs of GI Origin
The mTOR inhibitor everolimus, which is approved for the treatment of pancreatic NETs, has demonstrated efficacy against NETs in the GI tract and those of unknown origin, according to a subgroup analysis of the international phase IIII RADIANT-4 trial (Abstract 315).
Patients randomized to receive everolimus (10 mg/day) had approximately a doubling in progression-free survival (PFS) versus placebo in this post-hoc analysis. In the primary analysis of RADIANT-4, presented at the European Cancer Congress, everolimus reduced the risk of progression by 52% among patients with advanced GI and lung NETs (P < 0.00001).
“This was quite a stunning finding—a 7-month improvement in PFS. We are now looking in detail at the GI subgroup,” said Simron Singh, MD, MPH of Sunnybrook’s Odette Cancer Centre in Toronto, Canada, who presented the latest findings to the media.
The current analysis included 175 patients with previously treated advanced GI NETs and 36 patients with NETs from an unknown site. All patients had non-functional tumors, meaning the tumors were causing few or no symptoms initially.
In the overall population of this subanalysis, everolimus reduced the risk of disease progression by 40% or more, compared to placebo. Median PFS was 13.1 months versus 5.4 months among patients with GI tumors (HR =0.56) and 13.6 versus 7.5 months, respectively, among those with tumors of unknown origin (HR = 0.60).
“This was clearly a significant improvement in stopping tumors from growing with everolimus,” Dr. Singh commented.
When the researchers examined the findings in the midgut (ileum, jejunum, cecum, duodenum, appendix and small intestine) versus non-midgut (stomach, colon, rectum) locations, they found relative risk reductions of 29% and 73%, respectively, favoring everolimus, he said.
Additionally, prior treatment with an SSA did not reduce the benefit of everolimus, as the relative risk reduction was approximately 50% in groups with and without prior treatment. “Patients appeared to benefit from everolimus across the board,” he said.
The most common adverse effects with everolimus were those familiar to the drug—stomatitis, diarrhea, peripheral edema, and fatigue.
“This study in advanced progressive NETs suggests everolimus is a new, effective, exciting treatment option,” Dr. Singh concluded.
Dr. Krishnamurthi commented on the results. “While everolimus is already approved for treating pancreatic NETs, these results demonstrate that it may also be effective for a broader group of patients. The findings are important, showing an improvement in the risk of progression by more than 40%, without severe toxicity. This is a welcomed finding for patients with limited systemic treatment options.”
NETs in Midgut Benefit from Radiolabeled SSA
A novel radiolabeled SSA, 177Lu-DOTA0-Tyr3-Octreotate (177Lu-Dotatate) (Lutathera), reduced the risk of disease progression or death by 79% in an international phase III study of previously treated, advanced NETs of midgut origin (Abstract 194).
177Lu-Dotatate belongs to a fairly new therapeutic class known as peptide receptor radionuclide therapy (PRRT). With 177Lu-Dotatate, an SSA is attached to a radioactive molecule, enabling targeted delivery of radiation to tumors, explained Jonathan R. Strosberg, MD, of Moffitt Cancer Center, Tampa, Florida.
“There have been several generations of PRRTs. 177Lu-Dotatate is the latest, and it has a relatively favorable therapeutic index compared to previous generations,” Dr. Strosberg indicated.
“NETTER-1 is the first trial to test a PRRT in a randomized, prospective fashion,” he said.
NETTER-1 randomized 230 patients who progressed after SSA therapy to 177Lu-Dotatate or to more SSA treatment with high-dose octreotide LAR 60 mg. Patients in the experimental arm were treated once every 8 weeks for a total of 4 administrations of 177Lu-Dotatate.
At the time of analysis, 23 patients in the experimental group had disease progression, compared to 67 in the octreotide group. Median PFS was not reached with 177Lu-Dotatate but was 8 months with octreotide LAR (HR = 0.21; P < 0.0001).
“The study met its primary endpoint in extremely impressive fashion,” Dr. Strosberg commented in the presscast. “With roughly a year and a half of follow-up, the expected median PFS is likely to be longer than 3 years.”
Response rates were also higher with 177Lu-Dotatate, 19% versus 3% (P < 0.0004). While this rate may sound low, he explained that NET patients are very resistant to systemic therapy, and response rates to other treatments “are in the single digits.”
“This is the only large study showing double-digit response rates in midgut NETs, and the difference is highly significant,” he said.
Serious adverse events were reported in 26% of the experimental arm and 24% of the control arm. At the Symposium, Dr. Strosberg will provide more detail on these.
To date, 13 patients in the experimental arm have died, versus 22 in the control arm (P < 0.019), a numerical trend that does not yet meet statistical significance for this interim analysis, he said, “but is suggestive of an improvement” in overall survival.
Dr. Krishnamurthi commented that NETTER-1 shows 177Lu-Dotatate to have “an impressive ability to slow the growth of midgut tumors progressing on an SSA.” She was further impressed with the response rate in a population typically unresponsive to systemic treatments. “It’s exciting to see this novel therapy,” she said.
Shorter Radiation Course Benefits Locally Advanced Rectal Cancer
For preoperative treatment of locally advanced rectal cancer, a short, 5-day course of radiation followed by chemotherapy may be as effective as standard chemoradiation, which delivers radiation over about 5 weeks, with concurrent chemotherapy typically given in the 1st and 5th weeks, Polish investigators are reporting at the Symposium (Abstract 489).
The phase III study by the Polish Colorectal Study Group found that 5 days of radiation followed by 3 cycles of chemotherapy prior to surgery achieved similar outcomes with less toxicity.
“The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” said Lucjan Wyrwicz, MD, PhD, of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.
The study enrolled 515 patients with stage cT3 or cT4 rectal cancer, assigning them to standard chemoradiation or to the short-course radiation regimen. All patients received FOLFOX4 (5-FU, leucovorin, oxaliplatin). In the experimental arm, 3 cycles of chemotherapy followed 5 days of radiation (5 x 500 cGy), while in the control arm chemotherapy was given concurrently with radiation, which was delivered over about 5 weeks. The protocol was amended partway through the study to state that the use of oxaliplatin (which is relatively toxic) was by physician discretion and was not mandated. Both groups underwent surgery approximately 12 weeks after starting radiotherapy.
The short-course approach achieved outcomes that were as good as, or better than, those of the conventional arm. The treatments conveyed the same ability to perform radical surgery and achieved similar disease-free survival, but the short-course was associated with less toxicity, Dr. Wyrwicz reported.
R0 resection (negative surgical margins), the primary endpoint, was achieved in 77% of the experimental arm and 71% of the control arm (P = 0.081), indicating a trend in favor of the short-course approach. Pathologic complete responses were achieved by 16% and 12%, respectively (P = 0.17).
Rates of disease-free survival and local failure at 3 years were, for the experimental and control arms respectively, 53% versus 52% (P = 0.85) ad 22% versus 21% (P = 0.82). Acute toxicities were observed in 75% and 83%, respectively (P = 0006), though rates of grade 3+ toxicities were similar at 23% and 21%, he reported.
While those endpoints were not significantly different, the Kaplan-Meier curves for overall survival separated at about 2 years and plateaued afterward, with 3-year survival rates of 73% with the short-course radiation modality and 65% with chemoradiation (P = 0.046).
This preliminary observation of an 8% absolute survival benefit warrants a closer look for factors that may be contributing to a survival benefit, he added.
“Despite the fact that the trial was negative—it did not show superiority of the short-course for radical resection rate—we showed for the first time that there is an alternative to standard chemoradiation lasting more than 5 weeks,” Dr. Wyrwicz commented.
According to Dr. Krishnamurthi, short-course radiotherapy has been more widely used in Europe than in the US, largely because of conflicting results of studies that have compared it to standard treatment. “But these results may lead to increased use of this method here,” she said. “We’re trying to fine-tune how we deliver treatment to patients prior to surgery, to maximize efficacy and convenience and minimize side effects.”
by Caroline Helwick
The 2016 Genitourinary Cancers Symposium will kick off this coming Thursday in San Francisco. At a pre-meeting press cast, investigators were enthusiastic about the meeting, which will focus on "patient-centric" care. They spoke about 3 separate studies: two related to prostate cancer and one in advanced kidney cancer.
Another Benefit of Aspirin?
Regular use of aspirin appears to lower the risk of developing and dying from lethal prostate cancer, according to a large observational study. Regular aspirin use did not, however, lead to a reduction in the overall incidence of prostate cancer.
Lead study author, Christopher Brian Allard, MD, Urologic Oncology Fellow at Brigham and Women's Hospital and Massachusetts General Hospital in Boston said: "It is premature to recommend aspirin to prevent lethal prostate cancer, but men with prostate cancer who may already benefit from aspirin's cardiovascular effects could have one more reason to consider regular aspirin use." He added that discussions with patients about aspirin should include bleeding risks versus benefits.
Previous studies of aspirin and prostate cancer have been equivocal. Dr. Allard said his is the first study to focus specifically on prevention of lethal prostate cancer and to clarify the potential role of aspirin in prevention of advanced disease.
The study was based on data from 22,071 men enrolled in the Physician's Health Study. Over 27 years of follow up, 3193 men were diagnosed with prostate cancer and 403 developed lethal prostate cancer, defined as metastatic disease or prostate cancer-specific death. Regular aspirin use was defined as 3 or more tablets per week (of any dosage).
A multivariate analysis adjusted for age, race, body mass index, and smoking status showed that regular aspirin use was protective in the overall trial, resulting in a 24% reduced risk of developing lethal prostate cancer versus no regular aspirin use. Among men with a diagnosis of prostate cancer, regular aspirin use after diagnosis was associated with a 39% reduced risk of dying of prostate cancer.
Regular aspirin use did not protect against developing prostate cancer, high-grade prostate cancer, or locally-advanced prostate cancer.
Dr. Allard and colleagues will study mechanisms by which aspirin reduces the risk of prostate cancer death. More research is needed to select subsets of men that would benefit from regular aspirin use and to determine the optimal dose.
Sumanta Pal, MD, ASCO spokesperson and moderator of the presscast pointed out that there may be one more benefit of aspirin beyond that seen in colorectal cancer and cardiovascular disease. "....It's thought-provoking that this low-cost medication may lower the risk from prostate cancer," he said.
New Blood Test May Guide Treatment Decisions
A preliminary study suggests that an experimental blood test based on a "liquid biopsy" may be useful for individualizing treatment decisions for men with advanced prostate cancer. The non-invasive assay scans a patient's blood for cancer cells (i.e., circulating tumor cells [CTC]), analyzing their shape and size as well as genetic makeup to predict whether patients can benefit from hormone-directed therapies such as abiraterone and enzalutamide
A "liquid biopsy" based on easily-obtained blood samples is much more convenient and comfortable for patients than invasive tumor biopsy. Also, this assay allows for earlier adjustments in therapy compared with an invasive tumor biopsy.
"Not all men respond equally to either enzalutamide or abiraterone, and some men don't respond at all. If this test is validated, it could be used to help select the treatment to which a patient is more likely to respond, sparing the toxicities that may result from an ineffective treatment," explained lead author Howard I. Scher, MD, chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.
For the test, a blood specimen is stained with dyes to distinguish normal blood cells from CTCs, and then the cells are scanned for morphology, "much like facial recognition software used at airport security," said Dr. Scher. "The software can quickly identify a cell by examining its features." The cells of interest can then be analyzed for genetic abnormalities.
In the study, 221 blood specimens were obtained from 179 patients with metastatic prostate cancer slated for treatment with either enzalutamide or abiraterone. Patients with a higher heterogeneity score (i.e., more variation in CTC appearance and genetic composition) had a poor response to hormone therapy. Compared with those with a low heterogeneity score, patients with high heterogeneity score had shorter median progression-free survival (5 months vs 17 months) and overall survival (9 months vs not yet reached).
Heterogeneity score was not associated with response to taxane chemotherapy.
Before this assay can be used in clinical practice, it needs to be validated in larger sample sizes. Then clinical studies are required to determine if results predict outcomes.
"Tumors change over time, and prostate cancer appears to become especially complex over time. This exciting preliminary study suggests a method that may help us profile individual cancers in real time... Eventually, we may be able to offer the right treatment to the right patient and personalize our selection of therapy," said Dr. Pal.
Cabozantinib Beats Everolimus in Advanced Kidney Cancer
Cabozantinib achieved greater benefit than everolimus, the standard of care, in patients with previously treated advanced kidney cancer, according to an updated analysis of the phase III METEOR trial. Results showed that progression-free survival (PFS) was significantly improved with cabozantinib across all subgroups. Cabozantinib's superiority was independent of risk category, metastatic sites, and number and types of prior treatments.
An interesting hypothesis-generating finding was that patients who failed on second-line checkpoint inhibitor therapy did especially well on cabozantinib versus everolimus. But this included only a small number of patients (n=32) and needs further study.
Although current treatments can help patients with advanced kidney cancer, more effective treatments are needed, according to lead study author Bernard Escudier, MD, Institut Gustave Roussy, Villejuif, France. "Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope for patients with this aggressive cancer," he said.
Cabozantinib is approved for the treatment of thyroid cancer and is investigational in kidney cancer.
The study randomized 658 patients with advanced kidney cancer previously treatment with VEGFR inhibitor therapy (and 32 with previous immunotherapy) to receive cabozantinib or everolimus. Analysis of the first 375 patients found that cabozantinib improved median PFS versus everolimus: 7.4 months versus 3.8 months, respectively.
At the GU Cancers Symposium, Dr. Escudier will present results on all 658 patients enrolled in the trial, which basically replicate the findings in the first 375 patients, with a 48% reduction in risk of progression for those treated with cabozantinib versus everolimus.
Final overall survival results are expected to be presented at ASCO 2016.
An exploratory subgroup analysis found that cabozantinib was especially effective in patients with bone metastasis (considered difficult to treat), patients previously on sunitinib, and those who failed on prior checkpoint inhibitor therapy.
Common side effects with cabozantinib included diarrhea, fatigue, nausea and vomiting, decreased appetite, and hand-foot syndrome; the most common side effects with everolimus were fatigue, anemia, decreased appetite, cough, and dispend.
"These results exceed what we have seen in this setting. Virtually all patients derive benefit from cabozantinib. These striking early signs of success exemplify how precision medicine is paying off for patents," said Dr. Pal.
By Alice Goodman