Κυριακή, 5 Φεβρουαρίου 2017

ASCO ADVANCES OF THE YEAR

Immunotherapy is once again hailed as the "clinical cancer advance of year" by the American Society of Clinical Oncology (ASCO) in its annual report.
This is the second time that immunotherapy has won this accolade – it was also declared the clinical cancer advance of the year in last year's report.
It was chosen again this year in recognition of the "growing wave of progress" with immunotherapy that "has extended and improved the lives of patients, many of whom had few other effective treatment options."
During the past year (from November 2015 through October 2016), there has been a wave of new successes with checkpoint inhibitor immunotherapy, the report notes. "Research has proven this approach can be effective against a wide range of hard-to-treat advanced cancers previously considered intractable."
The report lists the progress made both with immunotherapy and with other therapies, much of which has already been reported by Medscape Medical News, as indicated in the links provided below.
Talk of "Cure" in Melanoma
"In just a few short years, immunotherapy has transformed the outlook" for patients with advanced melanoma, the report notes. "Given the lasting responses seen in a large proportion of patients who have received immunotherapy, experts are beginning to speculate that a cure may be within reach, at least for a fortunate few patients."
It highlights in particular new long-term data for pembrolizumab (Keytruda, Merck & Co). Follow-up of 655 patients enrolled in an early clinical trial showed a median survival of 23 months, and the 24-month survival rate was 49%. Tumors had shrunk in one third of the patients, and treatment responses lasted more than 1 year in 44% (JAMA. 2016;315:1600-1609).
These findings are similar to those previously reported for the similar agent, nivolumab (Opdivo, Bristol-Myers Squibb), which showed a 24-month survival rate of 43% among patients with advanced melanoma (J Clin Oncol. 2014;32:1020-1030).
Both survival rates were better than the rate seen with a different type of checkpoint inhibitor, ipilimumab (Yervoy, Merck & Co). An earlier analysis of pooled data from several trials found a median survival of only 11.4 months (J Clin Oncol. 2015;33:1889-1894).
Also in the previous year, improvement in survival was reported with adjuvant ipilimumab in patients with stage III melanoma for which surgical removal was possible, but a high dose of the drug was used (N Engl J Med, published online October 7, 2016).
Changed Paradigm in Lung Cancer
Immunotherapy has changed treatment paradigms in lung cancer, the report notes, adding that "the historical standard treatment of advanced lung cancer (ie, chemotherapy) has finally been displaced."
Pembrolizumab and nivolumab were both approved for second-line use in patients with previously treated non–small cell lung cancer (NSCLC) in 2015, and last year they were joined by a third drug, atezolizumab (Tecentriq, Genentech/Roche).
Pembrolizumab has now been approved for first-line use in NSCLC, after a trial showed improved survival compared with chemotherapy in patients who were positive for programmed cell death ligand 1 (PD-L1) (N Engl J Med, published online October 8, 2016).
"These findings will change initial treatment of metastatic NSCLC in that every newly diagnosed patient will need to be tested for PD-L1," the report comments. "Patients with high PD-L1 levels will likely receive immunotherapy rather than chemotherapy."
Further Approvals in Three New Cancer Types
The past year also saw approvals for immunotherapy in three new cancer types – bladder cancer, head and neck cancer, and Hodgkin's lymphoma.
The approval for bladder cancer for atezolizumab was the first new treatment for the disease in several decades, the report notes. This was an accelerated approval based on improved response rates compared to that seen historically with chemotherapy in an early clinical trial in patients with previously treated metastatic urothelial cancer, the most common type of bladder cancer (Lancet. 2016;87:1909-1920).
Nivolumab was approved for use in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck after it was shown to improve survival compared to chemotherapy and to have fewer adverse events, thereby improving quality of life for patients (N Engl J Med, published online October 8, 2016).
Hodgkin's lymphoma seems particularly susceptible to programmed cell death inhibitors, the report notes. Nivolumab was approved for Hodgkin's lymphoma after an early clinical trial showed that lymphoma went into remission in 53 (66%) of 80 patients and disappeared entirely in seven patients. (Lancet Oncol. 2016;17:1283-1294). Nearly all patients with classic Hodgkin's lymphoma who responded to the treatment had at least a 50% reduction in the amount of cancer in the body, and responses lasted 8 months on average. Pembrolizumab has also shown activity in this indication (J Clin Oncol. 2016;34:3733-3739).
Advances in Cancer Therapy Beyond Immunotherapy 
In addition to the growing success seen with immunotherapy, 2016 was marked by a wave of advances in precision medicine–based approaches," the report states. Among the advances highlighted are the following:
  • Midostaurin for acute myeloid leukemia (AML). Midostaurin (under development by Novartis) is a novel therapy targeting the FLT3 gene and is the first promising treatment for AML in more than 20 years, notes the report. A large trial, conducted in 717 previously untreated patients with FLT3-positive AML, showed that the addition of midostaurin to standard chemotherapy produced a large survival benefit, with median survival of 75 months vs 26 months with chemotherapy alone (Blood. 2015;126:6). Midostaurin also more than doubled the median event-free survival achieved with chemotherapy alone (8 v 3.6 months).
  • Inotuzumab ozogamicin for acute lymphoblastic leukemia (ALL). In a late-stage, ongoing trial, the rate of complete remission was more than twofold higher in the inotuzumab ozogamicin group compared with the standard therapy group (81% v 29%). There was also an increase in the median time until disease progression (5 v 1.8 months) and the median survival (7.7 v 6.7 months) (N Engl J Med. 2016;375:740-753). Inotuzumab ozogamicin (under development by Pfizer) is likely to become a new standard of care for older adult patients with relapsed or refractory B-cell ALL, the report predicts, although it also notes that the product has a major adverse effect, veno-occlusive liver disease, seen in 11% of patients.
  • Alectinib in ALK-positive NSCLC. Alectinib (Alecensa, Genentech) is a second-generation product approved for use in the 3% to 7% of NSCLC patients who test positive for anaplastic lymphoma kinase (ALK) and who have stopped responding to first-line treatment with crizotinib (Xalkori, Pfizer). It has also shown activity against brain metastases, and preliminary findings from an ongoing late-stage clinical trial (known as J-ALEX) suggest that alectinib may also be useful as first-line treatment in previously untreated patients with advanced, ALK-positive NSCLC (J Clin Oncol. 2016;34 [suppl; abstr 9008]).
  • New regimen halts multiple myeloma. The new three-drug combination comprising the novel antibody therapy daratumumab (Darzalex, Janssen Biotech) added to a standard combination of bortezomib (Velcade, Millennium) and dexamethasone (multiple brands) was hailed as a new standard of care in multiple myeloma after the CASTOR trial showed a 70% lower risk for cancer progression than the standard two-drug regimen of bortezomib plus dexamethasone. In addition, partial response rates were increased from 29% to 59% with the addition of daratumumab, and complete response rates were increased from 9% to 19% (J Clin Oncol. 2016;3204 [suppl; abstr LBA4].
  • New class of drugs for breast cancer. The novel targeted agents are inhibitors of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), which are involved in breast cancer resistance to hormone therapy. The first of these new drugs to be approved is palbociclib (Ibrance, Pfizer); ribociclib (Novartis) is in late clinical development. These drugs have showed improved progression-free survival in women with hormone receptor–positive, HER2-negative metastatic breast cancer that had worsened with prior hormone therapy (palbociclib was added to fulvestrant, ribociclib added to letrozole). It is not yet clear whether palbociclib or ribociclib will extend overall survival, because follow-up has not been sufficiently long, but these findings have already changed the standard of care for patients with hormone receptor–positive metastatic breast cancer, the report notes.
  • More effective treatments for kidney cancer. The METEOR trial showed improved overall survival in patients with relapsed renal cell carcinoma (RCC) with cabozantinib (Cometriq, Exelisis, Inc) in comparison with standard-of-care everolimus (Afinitor, Novartis) (Lancet Oncol.2016;17:917-927), and the results led to approval of cabozantinib for this indication. However, two studies conducted in patients who were treated after undergoing surgery showed contrasting results: the S-TRAC study showed improved progression-free survival with adjuvant sunitinib (Sutent, Pfizer Inc) in comparision with placebo (N Engl J Med. 2016;375:2246-2254), but the ASSURE study found no significant difference between sunitibib, sorafenib (Nexavar, Bayer), and placebo when used after surgery (Lancet. 2016;387:2008-2016). These drugs should not be used after surgery in the clinic until additional data are available to reconcile these differing, the report cautions.
  • Adding chemotherapy to radiotherapy extends survival in glioma. For patients with grade 2 glioma who were treated with radiotherapy and who underwent additional chemotherapy (procarbazine, CCNU/lomustine, and vincristine; PCV), overall survival was substantially longer(13.3 years vs 7.8 years with radiotherapy alone) (N Engl J Med. 2016;374:1344-1355). This RTOG 9802 study has led to a change in the standard of care for high-risk, low-grade gliomas, the report notes: PCV chemotherapy is now added to radiation therapy.
  • More effective regimen for neuroblastoma. Adding a secondautologous stem cell transplant to standard therapy can improve patient outcomes: at 3 years, cancer had not recurred in 61% of patients who had undergone two transplants, compared with 48% of patients who had undergone one (J Clin Oncol. 2016;34 [suppl; abstr LBA3]).
  • "Sideness" in colorectal cancer. An analysis of clinical trial data showed a big difference in survival between whose colorectal cancer begans on the left side of the colon rather than on the right side (J Clin Oncol. 2016; 34 [suppl; abstr 3504]), which was confirmed by further analyses (JAMA Oncol , published online October 20 and 27, 2016). Overall, patients with left-sided tumors had a 20% lower risk for death, which suggests that the location of the primary tumor should be considered when establishing prognosis and designing future clinical trials, the report comments.
  • Chemotherapy combo in pancreatic cancer. Adding capeticebine to gemcitabine for adjuvant treatment of resected pancreatic cancer improved survival to 28 months (vs 25.5 months with gemcitabine alone) in the ESPAC-4 study (J Clin Oncol. 2016;34 [suppl; abstr LBA4006]). Although the difference in survival was small, the addition of capecitabine increased the chance of surviving 5 years from 16% to 29%, the report notes. This trial has recently been published (Lancet, published online January 24, 2017), and the investigators suggest that the two-drug combination should be the new standard of care for resected pancreatic cancer.
  • New formulation in AML. The investigational product CPX-351 (Vyxeos, under development by Celator/Jazz) is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio that maximizes synergy. In a trial in older AML patients, the new formulation improved survival by 4 months compared with standard combination therapy (J Clin Oncol. 2016;34 [suppl; abstr 7000]).
  • Concerns about laparoscopic surgery in rectal cancer. Patients with early and locally advanced rectal cancer can be cured with surgery, provided the tumor tissue is completely removed. However, two large studies (the ACOSOG Z6051l trial [JAMA. 2015;314:1346-1355] and the ALaCaRT trial [JAMA. 2015;314:1356-1363]) have raised concerns that laproscopic surgery may not remove tumor tissue as completely as open surgery, which could increase the risk for relapse and for shortened survival. As a result, the report notes that "routine use of laproscopic surgery is not recommended for patients with stage II or III rectal cancer."
  • Longer hormonal therapy reduces breast cancer reduction. After surgery for early-stage, hormone receptor–positive breast cancer, taking an aromatase inhibitor for 10 years, rather than 5 years, further reduced the risk of recurrence (N Engl J Med. 2016,375:209-219).
Need for Federal Funding of Research
The report also highlights the need for "sustained, robust federal funding for continued research and innovation."
Approximately 30% of the research highlighted in the report was funded, at least in part, through federal dollars allocated to the National Institutes of Health or the National Cancer Institute, notes ASCO president Daniel Hayes, MD, in a foreword.
"Without this federal investment — unique internationally in scale, duration, and impact for decades — I fear we may lose the forward momentum needed to further the progress we see highlighted in this report," he comments.

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