The laudable progress of expanded treatment options for patients with cancer continued in 2019, with more than a dozen approvals by the US Food and Drug Administration (FDA) for new oncology drugs or new indications for existing drugs. Here is a look at 8 major clinical trials publishing results this year on cancer treatments—including immunotherapy, poly(ADP)ribose polymerase (PARP) inhibitors, and cyclin-dependent kinase (CDK) 4/6 inhibitors—that advanced, and in some cases transformed, patient care. Immunotherapy at 5 Years: KEYNOTE-001 and CheckMate 067 Not long ago, patients with metastatic non–small cell lung cancer (NSCLC) had bleak survival odds—the likelihood of living 5 years after diagnosis was 5% or less. The 2019 FDA approval of pembrolizumab as a first-line treatment for patients with stage III NSCLC signals just how far we have come. Results from the phase 1b KEYNOTE-001 trial of pembrolizumab as first-line monotherapy for advanced or metastatic NSCLC highlight its game-changing impact on patient prognosis. Data presented at the 2019 American Society of Clinical Oncology annual meeting demonstrated that close to 25% of patients receiving pembrolizumab who were treatment naive were alive at 5 years. "[The outcomes] speak to the durability of the treatment benefit and are clinically very important," said Suresh Ramalingam, MD, professor and deputy director of the Winship Cancer Institute of Emory University in Atlanta. KEYNOTE-001 included 550 patients with no EGFR or ALK gene mutations, 100 of whom were treatment-naive. For patients with tumors with a high expression of programmed cell death ligand 1 (PD-L1 ≥ 50%), survival odds improved: Almost 30% of patients who were treatment naive and 25% of previously treated patients with this PD-L1 status were alive at the 5-year mark. The drug was also generally well tolerated, with immune-related adverse events affecting 17% of patients and pneumonitis—the most serious side effect—occurring in less than 5% of patients. "This study raises the potential that a treatment might lead to a cure of metastatic lung cancers, which is a paradigm shift for a traditionally 'incurable' illness," said Mark G. Kris, MD, a medical oncologist specializing in lung cancer at Memorial Sloan Kettering Cancer Center in New York City. Immunotherapies are also transforming survival in melanoma. A recent analysis published in The New England Journal of Medicine reported that more than half of patients (52%) receiving nivolumab plus ipilimumab were alive at 5 years, compared with 44% receiving nivolumab and 26% receiving ipilimumab. This study expands on initial 2017 results from the CheckMate 067 study, which randomized 945 patients to one of these three immunotherapy regimens. Investigators reported almost 60% of patients in the combination therapy group were alive at 3 years compared with 52% and 34% in the nivolumab and ipilimumab arms, respectively. In fact, in 2018, the National Comprehensive Cancer Network guidelines added nivolumab/ipilimumab as a first-line option for patients with advanced melanoma. "The original CheckMate 067 study was practice changing, and the 5-year follow-up data are reassuring," said melanoma expert and study investigator Michael Postow, MD, of Memorial Sloan Kettering Cancer Center. "More than half of patients are alive 5 years from the start of treatment with nivolumab plus ipilimumab, which means that with immunotherapy, metastatic melanoma is no longer life limiting in about half of patients." The next step, Postow said, will be to understand whether combining immunotherapy with BRAF-directed targeted therapies would further improve overall survival. Recent trials have explored triplet therapy combining targeted inhibitors and immunotherapy, but Postow noted that oncologists still require larger studies before they change their treatment practices. "Combining targeted therapy and immunotherapy is a hot area in melanoma, but we're not at a point yet where patients should receive these triplets based on the available data," Postow said. Targeted Inhibitor Combination Therapy in CLL Recent data highlight the importance of targeted therapies for treating chronic lymphocytic leukemia (CLL). Venetoclax, approved this year to treat adults with CLL, and ibrutinib, approved in 2016 as first-line therapy for CLL, have both extended progression-free survival for patients. More recently, a phase 2 study published in The New England Journal of Medicine found that combining these two targeted drugs as first-line treatment for higher-risk, older adults with CLL yields even better outcomes and allows patients to forgo chemotherapy. In the trial, 80 patients with CLL who were treatment naive and had one or more high-risk genetic features were given 24 cycles of the combination regimen. After receiving just 12 cycles, however, almost 90% of patients had complete remission or complete remission with incomplete blood count recovery, and 61% reached remission with undetectable minimal residual disease. The progression-free survival at 1 year was estimated to be 98%, and the overall survival was 99%. Although the venetoclax/ibrutinib combination has not yet received FDA approval for patients with CLL, other venetoclax and monoclonal antibody options have—venetoclax plus obinutuzumab was recently approved for frontline treatment of CLL, as was venetoclax plus rituximab. "This combination of very effective low-intensity therapy has changed our practice in patients with CLL and is one of the most impactful findings in our field," said Ehab Atallah, MD, professor and section head of hematologic malignancies at the Medical College of Wisconsin. "Venetoclax in combination with a targeted antibody as frontline therapy in CLL will likely reach many patients." CDK 4/6 Inhibitors: MONARCH 2 In the past 2 years, the FDA has approved three CDK 4/6 inhibitors after studies demonstrated these agents improved progression-free survival and quality of life for patients with hormone receptor–positive metastatic breast cancer. MONARCH 2 demonstrated an overall survival benefit in patients with hormone receptor–positive, HER2-negative advanced breast cancer who received the recently approved CDK 4/6 inhibitor abemaciclib along with fulvestrant. In this randomized phase 3 trial, investigators found that patients given the combination regimen lived significantly longer than those receiving fulvestrant alone regardless of menopausal status (46.7 months vs 37.3 months, respectively). The most common adverse events associated with the combination regimen were neutropenia (29.9%), diarrhea (14.5%), leukopenia (11.1%), and anemia (9.1%). "The MONARCH 2 trial provides further evidence for the superiority of CDK 4/6 inhibitors added to hormonal therapy for advanced ER-positive breast cancer," said Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine. Although oncologists have likely already changed practice based on earlier MONARCH data showing significantly improved progression-free survival, Bruksky noted that the most recent data highlight that "these combinations should now be considered standard of care for advanced ER-positive breast cancer." PARP Inhibitors: PROfound and PRIMA "Perhaps the most exciting trial from this year was the first biomarker-driven treatment approach for treating metastatic castration-resistant prostate cancer," said Jorge Garcia, MD, director of the advanced prostate cancer research program at the Cleveland Clinic in Cleveland, Ohio. In the PROfound trial presented at the 2019 European Society for Medical Oncology meeting, investigators compared the efficacy of the PARP inhibitor olaparib with physician's choice of enzalutamide or abiraterone in almost 400 patients with DNA repair–deficient metastatic castration-resistant prostate cancer. These patients were further subdivided into two groups—those with BRCA1, BRCA2, and ATM mutations, and those with one of a dozen other DNA repair deficiencies. The investigators found that at 12 months, patients who received olaparib had improved median progression-free survival compared with those given hormonal therapy—7.39 vs 3.55 months, respectively, in the BRCA1, BRCA2, and ATM mutations group, and 5.8 vs 3.2 months in the overall population. An interim analysis also suggested an overall survival benefit for those receiving the PARP inhibitor. "The impact of this study on the field is huge," said Garcia, who has worked on the development of other PARP inhibitors. He added that this trial highlights "the importance of tumor genomics and biomarker-driven clinical research in advanced prostate cancer." Tanya Dorff, MD, head of the genitourinary cancers program at City of Hope in Duarte, California, noted that the PROfound trial represents a major shift in the treatment of prostate cancer. "We have been on the brink of personalized therapy for prostate cancer on the basis of genomic selection of patients," Dorff said. "This trial is really the first clear level 1 evidence that PARP inhibitors are superior to androgen-targeted therapy for patients with metastatic castration-resistant prostate cancer harboring DNA repair defects." PARP inhibitors have also become a promising option for women with recurrent or newly diagnosed advanced ovarian cancer regardless of BRCA mutation status. This year, investigators published phase 3 data on the use of the PARP inhibitor niraparib in patients with newly diagnosed ovarian cancer. Lead author Antonio González-Martín, MD, PhD, and colleagues randomized 733 patients who had responded to platinum-based chemotherapy to receive niraparib or placebo once a day for 36 months. The investigators found that overall progression-free survival was 13.8 months in the niraparib group and 8.2 months in the placebo group. Patients with homologous recombination deficiency had an even better response to the PARP inhibitor, with a progression-free survival of 21.9 months compared with 10.4 months in the placebo group. "[The PRIMA study] has a greater chance of changing first-line maintenance [therapy] for ovarian cancer, particularly because it seems to show efficacy regardless of BRCA status in the recurrent setting, as we previously knew, and now as primary maintenance [therapy]," said Shannon M. Grabosch, MD, assistant professor of gynecologic oncology at the Saint Louis University School of Medicine in St Louis, Missouri. Anil K. Sood, MD, professor of gynecologic oncology and cancer biology at The University of Texas MD Anderson Cancer Center in Houston agreed that based on the PRIMA study, "PARP inhibitors have the potential to help a broader set of patients." However, he also noted that understanding the role of biomarkers in guiding therapy for specific subgroups versus treating all patients will require additional work. Triplet Therapy: BEACON Patients with metastatic colorectal cancer (CRC) who have the BRAF V600E mutation—as many as 15%— tend to have more aggressive disease and worse survival odds. Finding a drug regimen that can improve survival in patients with this advanced subtype of CRC has been a challenge. The BEACON trial, published this year in The New England Journal of Medicine, showed that a triplet regimen did lead to an overall survival benefit in these patients. The trial compared how triplet therapy with the BRAF inhibitor encorafenib, the MEK inhibitor binimetinib, and the EGFR inhibitor monoclonal antibody cetuximab fared against doublet therapy with encorafenib and cetuximab and physician's choice of two conventional chemotherapy options. After randomizing 665 previously treated patients to one of these treatment arms, investigators observed that the triplet option led to significant improvements in overall survival compared with chemotherapy. They reported a median overall survival of 9 months for patients receiving the triplet therapy compared with 8.4 months in the doublet group and 5.4 months in the chemotherapy group. Based on these data, the National Comprehensive Cancer Network guidelines added the triplet regimen for the treatment of metastatic CRC this year. "Triplet therapy is now the preferred second- or later-line strategy for these patients who are first treated with chemotherapy," said Benjamin Weinberg, MD, assistant professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC. "This option is attractive because it uses three targeted drugs and no chemotherapy." Although the triplet regimen improved overall survival by nearly 5 months compared with chemotherapy, the results were not as robust as many in the field had anticipated based on early data, according to Alan P. Venook, MD, Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California San Francisco. However, Venook noted that the regimen will still likely become a new standard for these select patients. "The lower toxicity and improvement in survival moved the regimen to the front of the class for these patients and is worth talking about, but the results also show how difficult it is to advance the field," he said. Skipping Radiotherapy: RADICALS-RT Should men with prostate cancer receive radiotherapy after surgery? It's a question that has troubled oncologists for years. Now data from the largest ever trial of postoperative radiotherapy in prostate cancer are helping provide some much-needed guidance. The late-breaking results of the RADICALS-RT trial presented at the 2019 European Society of Medical Oncology meeting showed that men can often be spared radiotherapy after surgery. Investigators found that men who underwent radiotherapy following prostatectomy and those who had radiotherapy only when the cancer returned experienced no difference in disease recurrence at 5 years. In that period, progression-free survival was similar in both groups—85% for men who received radiotherapy after surgery and 88% for men who were monitored. According to first author Chris Parker, of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, the study provides strong evidence that "observation should be the standard approach," with radiotherapy reserved for when the cancer returns. This strategy, Parker said, can help avoid the adverse effects of radiotherapy, which may include urinary leakage and narrowing of the urethra. According to genitourinary cancer specialist Dorff, before this trial, oncologists knew that some of the men who received adjuvant radiotherapy would not benefit from the therapy. "By tracking prostate-specific antigen levels and treating early relapse, we can now spare some men treatment that is unnecessary, which is really important," she said. Source
