Treatment advances across the spectrum of cancers have continued at a rapid pace. Lung cancer experienced significant treatment breakthroughs this year, primarily in immunotherapy, as it has in the past several years. Other immunotherapy trials brought new treatment options to patients with a range of solid tumor and blood cancers. In addition, in 2018, a Nobel Prize was awarded to the researchers who found that the immune system could be harnessed to attack cancer, highlighting the significance of research advances seen in this area.
Progress in treatment was also seen in systemic chemotherapy, targeted chemotherapy, surgery, and radiotherapy.
This year, research expanded the reach and impact of multiple forms of immunotherapy. Key studies of checkpoint inhibitors showed survival gains when the medicines were offered earlier in the course of treatment and in combination with other treatments, including other immunotherapies and chemotherapy. In adoptive cell therapy, longer-term data provided deeper insight on the benefits and risks of this approach in various blood cancers. The year also brought the FDA approval of several new immunotherapies (Appendix Table A2).
Checkpoint inhibitors proven valuable as initial therapy for advanced lung cancer. In advanced non–small-cell lung cancer (NSCLC), two trials demonstrated that checkpoint inhibitor therapies have a role in first-line treatment. The phase III IMpower150 (ClinicalTrials.gov identifier: NCT02366143) trial27 tested combinations of carboplatin, paclitaxel, and bevacizumab (Avastin) with or without the immunotherapy agent atezolizumab (Tecentriq), which targets the programmed death ligand-1 (PD-L1) protein. Median progression-free survival was 8.3 months for all patients who received the standard treatment plus immunotherapy compared with 6.8 months for those who received conventional chemotherapy with bevacizumab.
In another phase III trial, KEYNOTE-189 (ClinicalTrials.gov identifier: NCT02578680),28 researchers randomly assigned participants to receive chemotherapy drugs pemetrexed and cisplatin or carboplatin, followed by the PD-1 inhibitor pembrolizumab or a placebo. Both 1-year overall survival rate (69.2% in the pembrolizumab group v 49.4% in the chemotherapy-alone group) and median progression-free survival time (8.8 months in the pembrolizumab group v 4.9 months in the chemotherapy-alone group) were greater among patients in the pembrolizumab group compared with patients who received chemotherapy alone.
Combination immunotherapy boosts renal cell cancer survival, established as new standard. The combination of two immunotherapy agents, nivolumab and ipilimumab, is used routinely in melanoma and is now being explored in other types of cancer. A phase III trial (CheckMate214; ClincialTrials.gov identifier: NCT02231749)29 evaluated this new combination immunotherapy regimen in patients with intermediate- or high-risk renal cell carcinoma, finding it improved the 18-month overall survival rate compared with the tyrosine kinase inhibitor sunitinib (Sutent), 75% for the combination v 60% for sunitinib. Remarkably, 9% of patients receiving nivolumab with ipilimumab had complete regression of the cancer.
Although not without the potential for serious toxicities, this combination of immunotherapies is now the standard of care for patients with higher risk metastatic disease. The combination recently received FDA approval in high- and intermediate-risk advanced renal cell cancer,30 but it has not yet been established as an effective treatment for patients with low-risk disease.
Combination immunotherapy can reduce brain metastases in people with melanoma. Advanced melanoma is one of the few cancers that often metastasizes to the brain. These metastases can cause severe neurologic symptoms and lead to death within a year.
A phase II federally funded study, CheckMate204 (ClinicalTrials.gov identifier: NCT02320058),31 looked at the combination of nivolumab and ipilimumab (the same combination tested for renal cell cancer) in people with melanoma who had untreated metastases in the brain. Clinicians observed 94 people for 14 months after completion of treatment and found that 26% of patients had no detectable brain metastases and 30% had some reduction in metastases. An impressive 82% of patients were alive after a year, whereas survival had previously been measured at weeks and months for patients receiving standard treatment (this study was funded, in part, by NCI).
Significant side effects were seen in 55% of people on the trial, some of which affected the central nervous system. However, the study authors noted that, as a result of the impressive benefits seen in this study, this checkpoint combination could be explored in other cancers that have spread to the brain.
Investigational PD-1 inhibitor shows promise for a skin cancer with few treatment options. In September 2018,32 the FDA approved a new anti–PD-1 checkpoint inhibitor, cemiplimab (Libtayo), for cutaneous squamous cell carcinoma. The approval was based on a nonrandomized phase II trial33 of 59 patients with metastatic disease in whom cemiplimab showed remarkable activity; tumors shrank in nearly half (28) of the patients enrolled onto the trial.
Cutaneous squamous cell carcinoma is the second most common skin cancer, with more than one million patients diagnosed annually. Although most of these cancers can be cured with surgical excision, this newer treatment could have an important impact for the small but significant proportion of patients with cancer that persists or metastasizes. Prior research has shown this cancer to be relatively unresponsive to other forms of treatment, including chemotherapy.
Pembrolizumab provides greatest benefit in head and neck cancers with high PD-L1 expression. The KEYNOTE-040 (ClinicalTrials.gov identifier: NCT02252042) phase III trial compared pembrolizumab (Keytruda) to standard chemotherapy in 495 people with recurrent or metastatic head and neck squamous cell carcinoma that was not responsive to platinum-based chemotherapy drugs.34 This trial further evaluated whether a marker—PD-L1 protein expression in more than 50% of tumor cells—affected outcomes.
The trial showed that pembrolizumab, compared with standard chemotherapy, modestly improved median overall survival time (8.7 v 7.1 months, respectively) if PD-L1 expression levels were greater than 1%. Median overall survival was approximately 4 months greater among people with tumors that expressed PD-L1 at a level greater than 50%. This is the first phase III trial to demonstrate the impact of PD-L1 expression on the efficacy of pembrolizumab in this form of cancer.
Chimeric antigen receptor T-cell (CAR-T) therapy trials show longer term benefits. In 2018, CAR-T therapy, also known as adoptive cell immunotherapy, was named the Advance of the Year by ASCO. Unlike checkpoint inhibitors, this form of immunotherapy boosts the ability of the body’s immune system to fight cancer using a patient’s own genetically reengineered T cells.
An early-phase clinical trial formed the basis of the 2017 FDA approval35 of the anti-CD19 CAR-T therapy tisagenlecleucel (Kymriah) for acute lymphoblastic leukemia, the most common cancer in children. CD19 is an important biomarker for this cancer because it is present on the surface of malignant B cells, thus making it an effective target for CAR-T cells.
More recently, a global phase II trial (ClinicalTrials.gov identifier: NCT03123939)36 confirmed preliminary data and established the feasibility of delivering this treatment to children. Of the 75 children in the trial, 81% showed decreased signs and symptoms of disease 3 months after completion of treatment. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Overall survival decreased over time but was still significant, with 90% of children living 6 months or longer and 50% of children living 12 months or longer.
Severe but transient adverse events were observed in 73% of the children treated with tisagenlecleucel. The next step will be to test this approach in larger numbers of children and in broader age ranges so that long-term persistence of the engineered cells can be studied along with long-term patient outcomes.
ZUMA-6 (ClinicalTrials.gov identifier: NCT02926833), a phase II trial of a second type of anti-CD19 CAR-T therapy, called axicabtagene ciloleucel (Yescarta), enrolled 111 adults with refractory large B-cell lymphoma.37 After a median time of 15.4 months, 82% of patients had decreased signs and symptoms of disease and 54% experienced a complete regression of disease. Furthermore, 52% of patients were alive 18 months after treatment. There were some significant adverse effects, including myelosuppression, cytokine release syndrome, and neurologic events. The FDA approved the drug for use in this population in October 2017.38
In a third anti-CD19 CAR-T therapy trial (ClinicalTrials.gov identifier: NCT03483688), this time with a newer investigational approach, researchers isolated specific T cells that express a CD19-directed chimeric antigen receptor, called CTL019, from patients and re-engineered them in the laboratory. They reinfused the new cells into the patients as part of a phase II federally funded study.39 Clinicians tested the CTL019 therapy in 14 adults with relapsed or refractory diffuse large B-cell lymphoma and 14 adults with follicular lymphoma. Results showed that the re-engineered CTL019 cells rapidly induced complete remission in six patients (43%) with B-cell lymphoma and 10 patients (71%) with follicular lymphoma (this study was funded, in part, by NIH). These results suggest that anti-CD19 CAR-T therapy is a promising option for people with multiple, relapsed, and refractory diffuse large B-cell lymphomas whose survival expectancies have previously been limited.
Targeted Therapy Advances
Targeting medicines to specific gene mutations in a cancer cell, as opposed to administering systemic chemotherapy that can affect every cell in the body, is still an exciting and productive frontier in oncology. With more than a decade of trials and evidence at hand, targeted therapies are expanding to new types of cancer that have been resistant to more conventional approaches.
New EGFR inhibitor delays lung cancer progression. One of the more frequently mutated genes in lung cancer is EGFR, and it can mutate in different ways and at different locations along its stretch of DNA. Some of the mutations that occur are responsive to first-generation targeted therapies, such as gefitinib (Iressa) and erlotinib (Tarceva). However, resistance mutations commonly emerge during treatment with these agents.
Two recent trials tested a new, second-generation drug, osimertinib (Tagrisso), that was developed to treat NSCLC with resistant or less common EGFR mutations. The oral medicine was approved by the FDA in 2018 based on a phase III international trial, FLAURA (ClinicalTrials.gov identifier: NCT02296125),40 in which 556 patients with EGFR-positive, unresectable or metastatic NSCLC were randomly assigned to initial treatment with osimertinib or the standard EGFR-targeted treatments gefitinib or erlotinib. Progression-free survival in patients who received osimertinib was 18.9 months compared with 10.2 months in patients who received a first-generation EGFR inhibitor. A second trial of osimertinib, AURA (ClinicalTrials.gov identifier: NCT01802632),41 primarily explored safety and effectiveness (phase I/II) with two different dosages of the medicine (80 and 160 mg) and reported that patients who received the medicine did not experience disease progression for between 16 and 19 months, regardless of the dosage.
Together, the trials showed that osimertinib almost doubled the time to disease progression achieved with older medicines. On the basis of these data, osimertinib has become the new initial treatment of choice in patients with NSCLC with certain EGFR mutations, including those not responsive to older EGFR-directed therapies.
New protein-targeted therapy delays cancer progression and gains approval for certain advanced breast cancers. HER2/neu was the first gene mutation in breast cancer for which a targeted therapy, trastuzumab, was developed. Since trastuzumab’s approval by the FDA in 1998,42 a handful of other targeted drugs for breast cancer have been developed. Abemaciclib (Verzenio), a newer drug, inhibits activity of the CDK4/6 proteins that regulate the rate of cell division as opposed to targeting a specific gene mutation.
In two phase III trials, abemaciclib showed activity against previously treated metastatic hormone receptor–positive, HER2-negative breast cancer. The MONARCH 2 (ClinicalTrials.gov identifier: NCT02107703) clinical trial43 randomly assigned 669 women with breast cancer who had disease progression, despite prior endocrine therapy, to fulvestrant (Faslodex) plus abemaciclib or fulvestrant plus a placebo. Fulvestrant is a medicine that degrades the estrogen receptor. Women taking abemaciclib plus fulvestrant had a median progression-free survival time of 16.4 months compared with 9.3 months for women who received fulvestrant plus a placebo.
The MONARCH 3 (ClinicalTrials.gov identifier: NCT02246621) trial44 tested nonsteroidal aromatase inhibitors—either anastrozole or letrozole—plus either abemaciclib or a placebo in 493 women. In both trials, treatment with an aromatase inhibitor plus abemaciclib resulted in longer life without disease progression. The findings of these trials (and the previously conducted MONARCH 1 [ClinicalTrials.gov identifier: NCT02102490] trial) led to FDA approval in February 2018 of abemaciclib in combination with an aromatase inhibitor.45
Novel combination treatment shows promise for elderly patients with acute myeloid leukemia (AML). Combining medicines with innovative mechanisms of action can lead to effective therapies in certain unique or hard-to-treat groups of patients. In AML, this approach is being pursued to improve care for older patients who are generally not healthy enough to tolerate conventional therapies.
Medicines such as azacytidine (Vidaza) and decitabine (Dacogen), which affect the DNA methylation process, have shown some short-lived benefit in these patients. To further boost their therapeutic impact, researchers turned to an oral medicine called venetoclax (Venclexta), which provokes cancer cell death by targeting the BCL2 protein.
A phase I trial (ClinicalTrials.gov identifier: NCT02203773)46 combining azacytidine and venetoclax was designed to see whether this combination could boost remission of AML in older people. Of the 57 patients initially enrolled, 35 patients achieved either complete remission or complete remission with incomplete restoration of bone marrow function. These results were promising enough to convince the investigators to continue studying this combination in larger groups of people.
Medicaid Coverage of Clinical Trials Services
This past year saw the introduction of the CLINICAL TREATMENT Act (HR 6836 in the 115th Congress) by Representatives Gus Bilirakis (R-FL) and Ben Ray Lujan (D-NM). This important measure, which ASCO supported, would require states to cover the routine clinical care costs of participation in an approved clinical trial for Medicaid enrollees. Routine care costs include the nonexperimental costs of treating a patient who is participating in a clinical trial, such as routine physician visits and laboratory studies. Although Medicare and private and commercial payers already guarantee this coverage, Medicaid is the only major payer that is not required by federal law to do so. With Medicaid insuring nearly one fifth of the US population, it is critical to close this gap and ensure that Medicaid beneficiaries have access to trials that may be the best clinical option for many patients.
Other Therapeutic Approaches
Beyond immunotherapy and targeted treatments, clinical trials brought new advances in several hard-to-treat cancers using a broader range of treatment strategies.
New modified chemotherapy regimen proves more potent in pancreatic cancer. For patients with pancreatic cancer who have had surgery, the standard postsurgery treatment until now has been gemcitabine, a chemotherapy drug that blocks tumor cells from multiplying. Despite this treatment, more than 70% of patients typically experience cancer recurrence within 2 years of surgery. This year, a trial identified a new, more effective approach using a combination of chemotherapy drugs.
In a phase III clinical trial (ClinicalTrials.gov identifier: NCT01526135)47 493 postsurgery patients were randomly assigned to either gemcitabine or a modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy regimen. The modified version tested in this trial was more tolerable, with reduced dosages of some medicines to minimize toxicity.
At a follow-up of 33.6 months, the median length of time without recurrence of pancreatic cancer (disease-free survival) was much longer in the FOLFIRINOX group than in the gemcitabine group (21.6 v 12.8 months, respectively), as was the median overall survival (54.4 v 35.0 months, respectively). Both regimens were found to be safe; however, modified FOLFIRINOX was more effective, albeit with higher toxicities. On the basis of this trial, modified FOLFIRINOX is now considered the standard of care after pancreatic cancer resection.
Less is more for certain ovarian cancers. In ovarian cancer, a recent trial (ClinicalTrials.gov identifier: NCT 00565851)48 helped resolve an ongoing debate about whether aggressive surgery is beneficial. This phase III clinical trial evaluated the benefit of secondary surgery for women with ovarian cancer that was successfully treated with platinum-based chemotherapy, with or without bevacizumab, in patients who were physically able to undergo additional surgical resection.
Researchers randomly assigned 485 women to secondary surgery followed by paclitaxel and carboplatin chemotherapy or chemotherapy with no additional surgery. There was no increase in survival with additional surgery; the median overall survival time was 53.6 months for patients who received the secondary surgery compared with 65.7 months for patients who only received chemotherapy.
These findings may be practice changing, as earlier studies and conventional wisdom previously supported secondary cytoreductive surgery. Although survival was over a year longer with just chemotherapy, the results need to be confirmed by studies that are now ongoing.
Two drugs show promise in men with prostate cancer resistant to hormone therapy. For men with early-stage prostate cancer, there is evidence demonstrating the benefits and risks of watching and waiting before commencing treatment. If prostate-specific antigen (PSA) levels rise, indicating that the cancer has progressed, the disease is typically treated with radiation, surgery, or drugs that block the androgen hormones that fuel the cancer’s growth. In patients who have received hormone therapy, however, if such cancers do not respond, researchers have determined that approximately 40%, or more than 250,000 men in the United States, will develop metastases and potentially die within a 16-month time interval.
Two phase III trials (ClinicalTrials.gov identifier: NCT01946204 and NCT02003924, respectively) evaluated apalutamide (Erleada)49 and enzalutamide (Xtandi)50 versus placebo in men with nonmetastatic prostate cancer who have increasing PSA levels and in whom the cancer is resistant to hormone therapy. These medicines work by blocking a key driver of prostate cancer, the androgen receptor, in a much more potent fashion than previous drugs.
Each study found a significant improvement in metastasis-free survival. Median metastasis-free survival was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group in one study. In the other study, median metastasis-free survival was 36.6 months in the enzalutamide group compared with 14.7 months in the placebo group.
These results led to the FDA approval of apalutamide in February 2018,51 as well as a broadening of the FDA label for enzalutamide in July 2018,52 meaning that it could be used for indications beyond the initial approval for late-stage castration-resistant prostate cancers. The researchers’ next aim is to analyze molecular and circulating markers from blood samples to identify patients who benefited the most from the therapies.
"Our nation must continue to invest in research so that we can make certain that cutting-edge cancer treatments are available to all patients. Federal research is the roadmap to renewed hope that you can bring to people’s bedsides each and every day."
—Representative Paul Tonko (D-NY)
The number of new FDA approvals in oncology continues at a rapid pace. From November 2017 through October 2018, the FDA approved 11 new cancer therapies and 39 new uses of cancer therapies (Appendix Table A2). In the same time frame in the previous year, there were 18 new cancer therapies and 13 new uses approved.