MAJOR CANCER ADVANCES IN 2014

This year in its annual review of clinical cancer advances, the American Society of Clinical Oncology (ASCO) has — for the first time — announced a winner. The transformation that has been seen in the treatment of chronic lymphocytic leukemia (CLL) has been crowned the Advance of the Year.

"This has truly been a banner year for CLL," said ASCO President Peter Yu, MD, a sentiment that we have already reported here at Medscape.

Four newly approved drugs "are poised to dramatically improve the outlook for patients with this disease," the society notes.

The new products include two immunotherapy drugs for use with the chemotherapeutic agent chlorambucil in previously untreated CLL: obinutuzumab (Genentech/Roche), which was approved as Gazyva in the United States in November 2013 and as Gazyvaro in Europe in July 2014; and ofatumumab(Arzerra, GlaxoSmithKline), which received full approval from the US Food and Drug Administration (FDA) in April 2014 following on from an accelerated approval in 2009 and similarly received a full European approval in July 2014.

While CLL is the most common adult leukemia, it disproportionately affects the elderly, who are often too frail to tolerate the standard treatment with the chemotherapy combination of fludarabine with cyclophosphamide plus the immunological agent rituximab, the report notes.

In previously untreated patients who were unable to tolerate the adverse effects of standard CLL treatments, each of these immunological therapies, given together with chlorambucil, has been shown to delay disease progression by around a year, the report notes. Both represent new first-line treatment options for CLL, it adds.

The other two news drugs for CLL are novel targeted agents for use in treatment-resistant or relapsed CLL: ibrutinib (Imbruvica, Pharmacyclics), a first-in-class inhibitor of Bruton's tyrosine kinase (BTK), approved for CLL in the United States in February 2014; and idelalisib (Zydelig, Gilead), a first-in-class phosphoinositide 3-kinase (PI3K) delta inhibitor, approved in the United States for CLL in July 2014. Both drugs were recommended for approval in Europe in July 2014.

Striking early clinical trial results with both of these novel agents suggest that they have the potential to transform the treatment of CLL, potentially eliminating the need for chemotherapy, the report notes.

The four new drugs "fill an enormous need for thousands of patients living with CLL," said Gregory Masters, MD, coexecutive author of the report. "For many older patients, especially, these [new] drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle," he commented in a statement.

Advances in Treatment of Cancer

In addition to the treatment advance seen in CLL, the report also highlights:

• Improved survival in low-grade glioma: Adding chemotherapy to radiotherapy extended survivalby more than 5 years, compared with radiotherapy alone (which has been the standard first-line treatment). The results come from a trial involving 250 patients; those treated with radiotherapy alone had a median overall survival of 7.8 years, compared with 13.3 years in patients who also received chemotherapy (procarbazine, lomustine and vincristine [PCV]). There was also a 4-year vs 10-year delay in disease progression. "Based on the dramatic survival improvements observed in this study, the combination of PCV chemotherapy and radiotherapy will likely become a standard treatment approach for patients with low-grade glioma," the report comments. However, temozolomide has largely replaced PCV for glioma since this trial began, and its role needs to be addressed, the report adds.
  • First-line chemotherapy in advanced prostate cancer: Results from the E3805 CHAARTED study, showing a survival benefit from adding chemotherapy to hormonal therapy upfront, were hailed as practice-changing and transformative when reported at the ASCO annual meeting. Traditionally, androgen-deprivation therapy (ADT) is the first-line treatment for advanced prostate cancer, and chemotherapy is added only once the cancer has become hormone-resistant. But this trial showed using chemotherapy up-front, at the same time as ADT, improved survival by around 10 months. "The substantial benefit of early chemotherapy warrants this combination being a new standard option, at least for men who have extensive disease and are fit for chemotherapy," the report comments.
  • Overcoming treatment resistance in lung cancer: Two novel investigational agents, AZD9291 (AstraZeneca) and C0-1686 (Clovis), have shown activity in phase 1 clinical trial patients with non-small cell lung cancer (NSCLC) harboring mutated EGFRwho have stopped responding to EGFR inhibitors because they have developed an additional EGFR mutation known as T790M. Also, the new drug ceritinib (Zykadia, Novartis) was approved in the United States in April 2014 for second-line use in patients with NSCLC harboring the ALK rearrangement, after it was shown to work in such patients who had developed resistance to crizotinib (Xalkori, Pfizer).
  • First treatment for chemo-resistant advanced stomach cancer: The angiogenesis inhibitor ramucirumab (Cyramza, Eli Lilly) was approved in the United States in April 2014 after it was shown to improve survival as a stand-alone therapy in the REGARD trial (Lancet. 2014;383:31-39).
  • Targeted drug for difficult-to treat thyroid cancer: The investigational drug lenvatinib (Eisai) has shown promising activity in differentiated thyroid cancer that is resistant to radioactive iodine therapy, which develops in about 5% to 15% of patients. In the SELECT study, the drug delayed disease progression by 15 months and resulted in tumor shrinkage in about two-thirds of patients. Lenvatinib is the second drug to show activity in this patient population; sorafenib (Nexavar, Bayer) was approved for this indication in 2013.
  Advancer in Cancer Immunotherapy
  "Researchers have reported remarkable results with both antibody and cell-based immunotherapies," the report comments, and highlights:
  • Immunotherapy for earlier-stage melanoma: The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) was FDA approved in 2011 for advanced melanoma that cannot be surgically removed or has metastasized; recent results from the EORTC 18071 trial show benefit in earlier-stage melanoma to prevent disease recurrence after surgery. However, adverse effects were considerable, so further work is needed to fully assess the balance of benefits and risks of this treatment, the report comments.
  • Immunotherapy makes steady headway in lung cancer: Clinical trial results are showing activityin lung cancer with three drugs that act on the programmed death-1 (PD-1) or the PD-1 ligand (PD-L1) pathway. Two of these drugs — pembrolizumab (Keytruda, Merck & Co) and nivolumab (Opdivo, Bristol-Myers-Squibb) — were recently approved for melanoma, and the third drug is the investigational agent MEDI4736 (MedImmune/AstraZeneca).
  • Breakthrough for relapsed leukemia with T-cell therapy, specifically chimeric antigen-receptor-modified (CAR) T-cells, which involves reprogramming the patient's own T-cells so that they home in on and destroy leukemic cells in a one-time treatment. The report highlights results with two investigational products: 19-28z CAR CD19 (developed by National Cancer Institute researchers, now collaborating with Kite Pharmaceuticals); and the CTL019 CAR T-cell therapy (University of Pennsylvania researchers now collaborating with Novartis).
  Advances in Rare Cancers
  • First viable alternative to surgery for rare joint disorder, pigmented villonodular synovitis (PVNS), in which benign tumors within the joints cause gradual destruction. The only current treatment is surgery, which can include joint replacement and limb amputations in severe cases. Two investigational agents have shown promise in these patients in small clinical trials. PLX3397 (Plexxikon) showed tumor shrinkage in 11 of 14 patients, with marked improvement in pain, joint stiffness, and daily activities, while RG7155 (Roche) showed tumor shrinkage in seven of 10 patients.
  • Activity in rare form of ovarian cancer, recurrent sex cord-stromal tumors of the ovary, seen with bevacizumab (Avastin), which is already marketed for several tumors types. In a small study, the drug shrank tumors in six of 36 patients and delayed disease progression for an average of 9 months (Cancer. 2014;120:344-351). Although preliminary, these results warrant further study of bevacizumab in this setting, the report comments.
  Advances in Prevention of Cancer
  • Anastrozole in breast cancer prevention: In a clinical trial conducted in women at high risk for the disease (e.g., because of high-density breast tissue or family history), the aromatase inhibitor anastrozole halved the risk of developing breast cancer; 2% of women on the drug developed the disease, compared with 4% on placebo. The magnitude of this effect is similar to that already seen in previous trials with tamoxifen, raloxifene, and exemestane, the report notes. At present, only tamoxifen and raloxifene are FDA approved for use in breast cancer prevention, it adds.
  • Recommendation for lung cancer screening from the US Preventative Services Task Force, which ASCO sees as "an important first step toward eventual widespread implementation of low-dose CT lung cancer screening in the United States and securing related health insurance coverage, both of which would have a dramatic impact on reducing lung cancer deaths."
  Advances in Patient Care
  • Early initiation of palliative cancer improves patient well-being: Palliative care is often offered too late, the report comments, typically in the last 2 months of life after all curative treatments have been exhausted. A recent study in 500 patients underscores the importance of early palliative care for patients with advanced cancer, showing that it improved spiritual well-being, quality of life at the end of life, symptom severity, and satisfaction with care (Lancet. 2014;383:1721-1736).
  • Preserving fertility during breast cancer treatment by adding a hormone drug to chemotherapy: The POEMS trial used goserelin (Zoladex, AstraZeneca) in women with hormone-receptor-negative disease, while another study, the PROMISE GIM6 trial, used triptorelin in patients with early-stage hormone-positive disease (J Clin Oncol. 2014;32[18 suppl];LBA505). Both studies reported more successful pregnancies among women who had the hormone treatment plus chemotherapy, compared with those who received chemotherapy alone.