Cancer experts looking back over the past 12 months have highlighted adoptive immunotherapy with chimeric antigen receptor (CAR) T cells as the most important clinical cancer advance of the year.
The announcement comes in Clinical Cancer Advances 2018, the annual report from the American Society of Clinical Oncology (ASCO) in which a team of cancer experts reviewed developments from November 2016 through October 2017.
In the course of that year, 31 new therapies for more than 16 types of cancer were approved by the US Food and Drug Administration (FDA).
Highlighted as the ASCO Advance of the Year is the first CAR T-cell therapy to be approved — tisagenlecleucel (Kymriah, Novartis) for acute lymphoblastic leukemia (ALL).
This product scored a double first, the report notes — it was the first adoptive cell immunotherapy and the first gene therapy for cancer to be approved by the FDA.
“Even more important than the historic significance of this achievement is the medical need this unique new therapy is poised to fill,” the authors write.
“Tisagenlecleucel may be the first treatment to truly turn the tables on recurrent pediatric acute lymphoblastic leukemia (ALL), one of the most common cancers in children,” they write. “In a clinical trial, in four of five patients, cancer went into remission after the treatment.”
This represents one of the most remarkable advances in the treatment of childhood cancer in the last decade.
This product “can eradicate relapsed ALL in children. This represents one of the most remarkable advances in the treatment of childhood cancer in the last decade and could dramatically change treatment paradigms for this disease,” the report authors enthuse.
The report notes that a second CAR T-cell therapy, axicabtagene ciloleucel (Yescarta, Kite Pharma), was approved to treat adults with certain types of lymphoma. More are in development, targeting other hematologic malignancies, including multiple myeloma.
“CAR T-cell therapy represents an exciting innovation that has the potential to transform cancer care,” the report states. However, “it also raises the ongoing issue of cost and reminds us that, as a community, we need to find solutions that will assure that every patient with cancer has access to the care they need.”
As previously reported by Medscape Medical News, CAR T-cell therapies come with an astronomical price tag (Kymriah is priced at $475,000 and Yescarta at $373,000), and there have been problems with arranging for reimbursement.
First Tumor Agnostic Therapy
Another milestone highlighted in the report is the first tumor agnostic therapy, a treatment based solely on the genetic makeup of a person’s cancer, rather than the type of cancer or its location in the body. This was the immunotherapy pembrolizumab (Keytruda, Merck & Co), which received accelerated approval by the FDA for use in any type of solid tumor in adults and children that has mismatch repair deficiency or high microsatellite instability.
The investigational agent larotrectinib (under development by Loxo Oncology) uses the same approach of targeting a genetic abnormality in many different cancers, but has a more precise mode of action. This drug, which acts on tropomyosin receptor kinase gene fusion, also seems to work across tumor types in both adults and children. Larotrectinib has the potential to become the first tumor agnostic targeted therapy for cancer, the report authors comment.
Patient Engagement Beats Drugs
The report highlights a recent study that showed that using a Webbased, patient-reported outcomes tool can help patients with advanced cancer live longer (JAMA 2017;318;197-198).
The Webbased tool enabled patients to report common symptoms in real time and triggered alerts to clinicians if symptoms worsened, which in turn led to action such as lowering the chemotherapy dose or administering supportive care. Patients with metastatic cancer who used the tool while receiving chemotherapy lived a median of 5 months longer than those who did not use the tool (31 vs 26 months, respectively).
“This improvement in survival was greater than that associated with nearly all cancer drugs that received FDA approval in 2016,” the report authors note.
A nationwide clinical trial that uses an updated tool that works on both personal computers and mobile devices is now underway in community practices across the United States, they add.
Advances in Lung Cancer Therapy
Several advances in the past year for the treatment of non–small cell lung cancer (NSCLC) are highlighted in the report.
For treatment of the most advanced form of the disease, two new therapeutic options were approved — the targeted therapy alectinib (Alecensa, Roche) for ALK-containing tumors (about 5% of total), and the immunotherapy pembrolizumab, which was approved for first-line use.
For earlier-stage disease, another immunotherapy, durvalumab (Imfinzi, AstraZeneca), dramatically slowed cancer growth in patients who had already undergone standard chemotherapy and radiotherapy. The results with durvalumab “mark the first advance in years” for the treatment of stage III locally advanced NSCLC, which accounts for a about a third of all NSCLC cases, the report notes.
“Immune checkpoint inhibitors have transformed treatment for advanced NSCLC,” the authors comment.
Immune checkpoint inhibitors have transformed treatment for advanced NSCLC.
There are currently three FDA-approved checkpoint inhibitors for previously treated NSCLC (nivolumab, pembrolizumab, and atezolizumab [Tecentriq, Genentech/Roche]). In addition, pembrolizumab is approved as an initial therapy for certain patients.
In clinical trials, patients who received these immunotherapies have lived longer, on average, than those who received standard chemotherapy. However, given that checkpoint inhibitors have been in use for only a few years, their impact on long-term survival is not yet known, the report notes.
Despite this qualifier, in the report, ASCO estimates that 250,000 years of life would be saved in the United States if all patients with NSCLC for whom checkpoint inhibitors are currently indicated received the treatment. The average number of years of life saved is 2.5, but as many as 25% of people who receive checkpoint inhibitors as an initial treatment and 10% of those who receive them as a second-line treatment may live well beyond 5 years after treatment initiation. (The estimates are from the ASCO Center for Research and Analytics.)
Paradigm Shift for Bladder Cancer
Bladder cancer is another type of cancer for which immunotherapy has transformed the outlook for patients, the report notes.
The most common type of bladder cancer, urothelial cancer, is difficult to treat at advanced stages. With standard chemotherapy, only 5% of patients are alive 5 years after diagnosis, it notes.
After 30 years of limited progress, the outlook for these patients is now improving with the arrival of immunotherapy. For some patients, immunotherapy offers a treatment option where none previously existed, and for others, it offers a chance to live longer with fewer treatment-related adverse effects.
Atezolizumab was the first immune checkpoint inhibitor to receive FDA approval for bladder cancer, but it was followed quickly by four others: nivolumab, avelumab (Bavencio, EMD Serono), pembrolizumab, and durvalumab.
Progress in Glioblastoma
Glioblastoma is one of the most common and deadliest types of brain cancer in adults. With current therapies, fewer than 1 in 10 patients live 5 years after diagnosis, the report notes. It highlights two new strategies that may possibly lengthen survival.
The first is tumor-treating fields (TTFs), low-intensity electrical fields applied through the skin from a device (Optune, Novocure Ltd) that patients wear on their head continuously at least 18 hours a day. This device was approved for the treatment of glioblastoma in 2015, after a clinical trial showed a survival advantage. That finding has now been confirmed by longer-term results. This trial was conducted in patients with newly diagnosed glioblastoma who were treated with surgery and radiotherapy, followed by chemotherapy with temozolomide(Temodar, Merck & Co). For patients who wore the TTF device, median survival was 21 months, vs 16 months for those who did not, and the 5-year survival rate was doubled, to 13% with TTF vs 5% without.
The second advance is the finding that adding temozolomide to a short course of radiotherapy results in longer survival than radiotherapy alone in elderly glioblastoma patients (median survival was 9.3 months vs 7.6 months). The quality of life was similar between the two groups.
This study also confirmed prior findings suggesting that a genomic biomarker, methylation of the O-6-methylguanine–DNA methyltransferase(MGMT) gene, predicts better outcomes in patients with glioblastoma. Among patients with methylated MGMT, median survival with radiotherapy plus temozolomide was 13.5 months compared with 7.7 months with radiotherapy alone.
Advances in Breast Cancer
For women with BRCA-related breast cancer, the PARP-inhibitor olaparib (Lynparza, AstraZeneca) was shown to be more effective than chemotherapy in the OlympiAD study (N Engl J Med. 2017;377:523-533). The FDA recently approved olaparib for use in BRCA-positive breast cancer, which account for up to 3% of all breast cancers.
In one trial, dual therapy with HER2 targeted agents (pertuzumab [Perjeta, Genentech] plus trastuzumab (Herceptin, Genentech) lowered the risk for invasive cancer (N Engl J Med. 2017;377:122-131), but the effect was modest, and there was an increase in adverse events, as previously reported by Medscape Medical News. The report authors comment that “these findings may set a new standard of care for some patients with node-positive, HER2-positive, hormone receptor–negative breast cancer who have a higher risk of developing invasive breast cancer.” The good news from this trial, they add, is that patients with HER2-positive breast cancer — the group of patients who used to have the worst prognosis — are doing so well on trastuzumab alone.
Several new studies gave support to extended hormone treatment (10 years vs 5 years) for patients with high-risk breast cancer. Extended treatment led to a reduction in the risk for relapse and cancer in the opposite breast (but did not improve overall survival). “Taken together, these findings support longer hormone therapy for women with early breast cancer who have a higher risk for recurrence on the basis of tumor features and patient-specific factors. Discussion of therapy duration should take into consideration the adverse effects the patient experienced during initial hormone therapy as well as ongoing health conditions,” the authors comment.
Progress in Prostate Cancer
For localized prostate cancer, last year saw results from several large studies that will help to “inform decision making,” the report notes.
In the landmark ProtecT trial (N Engl J Med. 2016;375:1415-1424), there was no difference in 10-year survival among patients who received surgery, radiotherapy, or active surveillance, although active surveillance was associated with a higher risk for cancer worsening and metastasis.
Another long-term study, the PIVOT trial, found that surgery did not reduce the risk for death compare to active surveillance, but men who underwent surgery had more sexual dysfunction and urinary incontinence through 10 years (N Engl J Med. 2017;377:132-142).
Two other studies provided details on the adverse events following the various treatments and compared quality of life after radical prostatectomy, external-beam radiation therapy, and active surveillance (JAMA. 2017;317:1126-1140, 1141-1150).
“Taken together, these findings from clinical trial participants as well as real-world patients will help clinicians better counsel patients about the risks and benefits of various treatments for localized prostate cancer,” the report authors comment.
For advanced prostate cancer, a new standard of care was established by two large clinical trials, known as LATITUDE and STAMPEDE, which showed a survival benefit from adding abiraterone (Zytiga, Janssen) to standard androgen-deprivation therapy (ADT) (N Engl J Med. 2017;377:352-360, 377:338-351). In the STAMPEDE trial, the 3-year survival rate was 76% with standard therapy alone and 83% with standard therapy plus abiraterone.
In addition, a large clinical trial (RTOG 9601) found that adding ADT (with bicalutamide) to radiotherapy helps men who experience a local recurrence after surgery live longer: the survival rate at 12 years was 76% with ADT plus radiotherapy vs 71% with radiotherapy alone (N Engl J Med. 2017;376:417-428). Although the drug used in this trial, bicalutamide, is now little used, “these findings provide strong evidence to support the combination of ADT with radiation therapy for men who experience a local recurrence after surgery,” the report authors comment.
Several Instances Where “Less Is More”
Less is more when it comes to chemotherapy, as shown in findings that are relevant to approximately 400,000 patients with stage 3 colon cancer worldwide, the authors comment.
In a meta-analysis of six trials with a total of 12,800 patients, conducted by the International Duration Evaluation of Adjuvant chemotherapy (IDEA) collaboration, that compared 3 months of chemotherapy with 6 months of chemotherapy, outcomes were similar, but there was significantly less peripheral neuropathy with the shorter course.
“These findings should inform conversations between oncologists and their patients,” the report authors write.
“For patients with lower-risk stage 3 colon cancer, the shorter 3-month course will likely become the new standard of care,” they say. “For patients with higher-risk cancer, decisions on shorter-duration therapy will have to be carefully weighed against the risks of recurrence, patient ability to tolerate chemotherapy, and patient preferences.”
Less can also be more when it comes to surgery, as reported in the following:
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In melanoma, the large MSLT-I trial showed that removal of additional lymph nodes does not improve survival, and although it lowers the risk for regional recurrence, it leads to more health complications, especially lymphedema (N Engl J Med. 2017;376:2211-2222).
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In breast cancer, new guidelines on negative margins led to fewer second surgeries after lumpectomy. A large population-based study found that from 2013 to 2015, the rate of initial lumpectomy remained stable at 67%, but the rate of second breast surgery declined by 16%, and fewer women underwent a subsequent mastectomy (JAMA Oncol. 2017;3:1352-1357).”This study demonstrates the important role of clinical practice guidelines in reducing overtreatment,” the authors comment.
And less is more when it comes to radiotherapy for patients with human papillomavirus (HPV)–related oropharyngeal cancer. Two separate clinical trials found that lowering the standard radiation dose by 15% to 20% in patients with a favorable prognosis (ie, those in whom a complete clinical response is achieved with initial chemotherapy) does not compromise survival (J Clin Oncol. 2017;35:490-497; Lancet Oncol. 2017;18:803-811).
“If confirmed in a larger clinical trial, these findings will lead to a change in the standard of care for patients with lower-risk, HPV-related oropharyngeal cancer (eg, those with a minimal smoking history and small tumor size),” the authors comment.
ASCO. ASCO Clinical Cancer Advances 2018.
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