Our understanding of the biology of cancer continues to grow rapidly, leading to new types of targeted treatments and novel therapeutic approaches. In the past year, treatments were combined in new ways, optimal dosing and scheduling were identified for existing treatments, and adverse events were reduced. Researchers also identified groups of patients more likely to benefit from specific treatments and made strides in surgery and radiotherapy.
“I never thought in my life that I would see patients with lung cancer cured, but this is now a reality for many people. It is an amazing feeling to see how far we have come through research and development.” —Gladys Rodriguez, MD
Dr. Rodriguez is an oncologist at the START Center for Cancer Care in San Antonio, Texas, and is featured in ASCO’s I Live to Conquer Cancer campaign. Learn more about why Dr. Rodriguez lives to conquer cancer.
Aggressive Treatment Improves Disease Control in Certain Patients With Stage IV Lung Cancer
A growing body of evidence suggests that more aggressive treatment with radiation (known as local consolidative therapy) or surgery extends survival for select patients with stage IV non–small-cell lung cancer (NSCLC) with spread limited to a small number of metastases (oligometastatic) outside of the lungs. The concept behind local consolidative therapy is that oligometastatic disease may represent an intermediate state between locally advanced disease and unequivocally metastatic disease. Small trials have suggested that ablative therapy (surgery or stereotactic radiation) to a few sites of metastatic disease (local consolidative therapy) extends progression-free survival.
In 2016, researchers published early data from a randomized study that examined this approach. The trial was closed early after it demonstrated an 8-month benefit in progression-free survival for patients who received local consolidative therapy compared with maintenance therapy or observation. In 2019, researchers published updated results from the phase II randomized trial (ClinicalTrials.gov identifier: NCT01725165)22 of 49 patients with stage IV NSCLC with up to three metastatic sites and stable disease for 3 months after first-line systemic therapy. Patients in the study were randomly assigned to maintenance therapy/observation or local consolidative therapy (surgery or radiotherapy) and observation/maintenance therapy. This study was funded, in part, by the NCI.
The median progression-free survival was more than three times longer for patients undergoing local consolidative therapy compared with the maintenance/observation group—14.2 months v 4.4 months. Likewise, median overall survival more than doubled in the local consolidative therapy group (41.2 months v 17.0 months). The findings are important because they support the notion that the oligometastatic state represents a unique tumor biology that may be managed effectively with local therapy. No patient reported severe adverse events (grade 3 or greater) beyond those reported in the earlier publication. This approach is now being tested in phase III randomized trials.
Open Surgery Proves Superior to Minimally Invasive Surgery for Early-Stage Cervical Cancer
Minimally invasive surgery has largely been adopted for the surgical treatment of early-stage cervical cancer. Guidelines in the United States and Europe, however, allow for either laparotomy (open surgery) or laparoscopy (minimally invasive surgery performed with either conventional or robotic techniques) to be used for radical hysterectomy in patients with early-stage (IA1 to IIA) cervical cancer. Two important studies recently showed superior survival for patients who received open surgery to treat cancer.
In the LACC trial (ClinicalTrials.gov identifier: NCT00614211),23 researchers reported worse progression-free survival and overall survival with minimally invasive surgery in a randomized controlled trial comparing the approach to open abdominal radical hysterectomy in more than 600 women with early-stage cervical cancer (IA1, IA2, or IB1). At 3 years, progression-free survival was 91.2% v 97.1% and overall survival was 93.8% v 99% with minimally invasive surgery and open surgery, respectively. These differences remained statistically significant after adjusting for relevant prognostic factors.
Similar findings were reported in a second study based on retrospective data from the National Cancer Database.24 Half of the more than 2,000 women in the dataset underwent minimally invasive radical hysterectomy and the remainder had open surgery. The 4-year mortality rate was higher among patients treated with minimally invasive radical hysterectomy—9.1% v 5.3%.
Together, these studies call into question whether laparoscopic hysterectomy for early-stage cervical cancer should remain a standard of care. Further research is necessary to determine if there is a patient population for which this approach results in acceptable clinical outcomes.
Stereotactic Radiation Prolongs Survival in Patients With a Limited Number of Metastases
Patients with oligometastatic disease and a well-controlled primary tumor may be eligible for a curative treatment approach. The use of radiotherapy and/or surgery, called “local consolidative therapy,” has been suggested as an approach to treat limited cancer metastases with the intention of eradicating disease.
The phase II SABR-COMET trial (ClinicalTrials.gov identifier: NCT01446744),25 published in 2019, is one of the first randomized trials to compare stereotactic ablative radiotherapy with standard palliative care aimed at minimizing symptoms and preventing complications.
The trial included 99 patients with one to five metastatic lesions. Primary cancers were predominantly breast, colorectal, lung, or prostate. Overall survival in the stereotactic radiotherapy group was more than a year longer, 41 months, v 28 months in the standard of care group. Adverse events with radiotherapy were more common than with standard care. Only 9% of the 33 patients receiving standard care had an adverse event of grade 2 or more compared with 29% of the 66 patients receiving radiotherapy. The most common adverse events were fatigue, trouble breathing, and pain. In addition, three deaths in the radiotherapy group were considered to be treatment related. Phase III trials are needed to validate the findings, determine the number of metastases to treat, and identify how to balance improved cancer control with increased toxicity.
Trials Confirm Cisplatin Plus Radiotherapy as Standard Care for HPV-Positive Head and Neck Cancer
HPV-positive squamous cell carcinoma has a very good prognosis when treated with cisplatin and radiotherapy; however, cisplatin carries risk of severe acute adverse events and late toxicity. As a result, there has been substantial interest in treatment de-escalation strategies in HPV-driven head and neck cancer. Early trials of the targeted drug cetuximab in combination with radiation suggested both a survival and toxicity advantage for cetuximab.
Two complementary trials evaluated the noninferiority of cetuximab plus radiotherapy compared with cisplatin plus radiotherapy. Data from these trials turned out to be practice-changing: both showed that the combination of radiation and cetuximab led to worse outcomes than the combination of radiation and cisplatin. In addition, toxicities appeared to be similar with cetuximab.
After 2 years of follow-up in the 334-patient De-ESCALaTE trial (ClinicalTrials.gov identifier: NCT01874171),26 patients who received cisplatin had longer overall survival compared with those who received cetuximab—97.5% v 89.4%. There was no difference between the two patient groups in terms of severe adverse events (grade 3 or greater) that did not last long and/or were chronic.
The second trial (805 patients), RTOG 1016 (ClinicalTrials.gov identifier: NCT01302834),27 showed similar results, with 5-year estimated survival at 77.9% in the cetuximab group compared with 84.6% for the cisplatin group. The proportions of acute to moderate toxicity and late moderate to severe toxicity were lower for those receiving cisplatin compared with those receiving cetuximab. While surprising, the outcomes of these trials have defined cisplatin plus radiotherapy as the standard of care in patients with HPV-positive squamous cell carcinoma. This study was funded, in part, by the NCI.
ASCO’s Targeted Agent and Profiling Utilization Registry Study (TAPUR; ClinicalTrials.gov identifier: NCT02693535) continues to enroll patients and report findings on patient outcomes. TAPUR evaluates antitumor activity of commercially available, targeted anticancer drugs when used outside of their FDA-approved indications. It aims to identify new uses for existing, effective treatments that target tumor genomic profiles.
More than 2,350 participants have been registered and more than 1,700 treated with a TAPUR study therapy. Based on treatment responses in the first stage of the study, patient cohorts are either expanded to stage II for further study or permanently closed. Visit the TAPUR website to see the full list of patient cohort updates.
Antibody Drug Conjugate Delays Recurrence of HER2-Positive Breast Cancer
Trastuzumab emtansine (T-DM1) was approved by the FDA in 2019 for adjuvant (postoperative) treatment of patients with residual invasive disease after neoadjuvant (preoperative) treatment with a regimen that included a taxane and trastuzumab. T-DM1 only benefits patients with breast cancers that overexpresses a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. HER2 is overexpressed in roughly 14% of women with breast cancer.28
Trastuzumab, a monoclonal antibody directed against HER2, has been transformative in the care of patients with HER2-positive breast cancer since it was first approved in 1998. T-DM1 links the biologic drug trastuzumab with the chemotherapy drug emtansine. This allows for selective delivery of the chemotherapy drug into HER2-overexpressing cells, resulting in cell cycle arrest and apoptosis.
The 2019 approval of adjuvant T-DM129 came in response to the phase III KATHERINE trial (ClinicalTrials.gov identifier NCT01772472),30 which included nearly 1,500 patients. All patients had residual invasive disease following neoadjuvant treatment with taxane- and trastuzumab-based regimens and were randomly assigned in a 1:1 fashion to receive 14 cycles of adjuvant trastuzumab (the current standard of care) or 14 cycles of adjuvant T-DM1. Those who received adjuvant T-DM1 had a 50% lower risk of recurrence of invasive disease or death compared with those who received postoperative trastuzumab.
Immunotherapy Combined With Chemotherapy Delays Cancer Progression in a Group of Patients With Metastatic Triple-Negative Breast Cancer
In triple-negative breast cancer, the three most common types of receptors that drive breast cancer growth are not expressed—estrogen and progesterone receptors (ER and PR), and HER2. Those whose cancers are negative for ER, PR, and HER2, otherwise known as triple-negative breast cancers, have not been able to benefit from hormone-targeted or HER2-targeted therapies, and as a result, chemotherapy has been the only option for systemic therapy. Unfortunately, for patients with metastatic triple-negative breast cancer, prognosis is extremely poor, with average survival rates of 18 months or less from the time of metastatic diagnosis.
This past year, results from IMpassion130 were presented and published, (ClinicalTrials.gov identifier: NCT02425891)31 showing that combining the programmed cell death-ligand 1 (PD-L1) targeted therapy atezolizumab with a common chemotherapy (nanoparticle albumin-bound [nab] paclitaxel) improved progression-free survival in patients with triple negative breast cancer. In the entire study population, patients receiving the combination had a progression-free survival of 7.2 months, compared with 5.5 months for those who received placebo plus nab-paclitaxel.
Patients were stratified by PD-L1 immune cell (IC) status (positive or negative), and authors found that the benefit of atezolizumab was limited to the PD-L1 IC-positive population. In the PD-L1 IC-positive population, progression-free survival was 7.5 months with the combination and 5.0 months with nab-paclitaxel alone. In the PD-L1 IC-positive population, progression-free survival was not markedly different between arms. Atezolizumab plus nab-paclitaxel was approved by the FDA in March 2019 for this population and is already in widespread use.32
In June 2019, updated survival data from IMpassion130 were made available, showing that for the PD-L1 IC-positive patients, the addition of atezolizumab significantly improved overall survival (25 months v 18 months), whereas for PD-L1 IC-negative patients, there was no difference between arms (19.7 v 19.6 months). The study highlights the importance of continued research into biomarkers of immunotherapy responsiveness and into different subsets of triple-negative disease.
“Thanks to advances in metastatic breast cancer research, we now have effective treatments that are easy to take with fewer side effects, improving quality of life for our patients." —Stephanie Graff, MD
Dr. Graff is an oncologist at Sarah Cannon Cancer Institute at HCA Midwest Health Overland Park, Kansas, and is featured in ASCO’s I Live to Conquer Cancer campaign. Learn more about why Dr. Graff lives to conquer cancer.
Adding Ribociclib to Endocrine Therapy Improves Survival in Young Women With Advanced ER-Positive/HER2-Negative Breast Cancer
Premenopausal women with breast cancer tend to have more aggressive disease with worse survival than those who are postmenopausal, and they are often under-represented in clinical trials compared with older women. Research suggests that breast cancer in premenopausal women may be biologically different. Despite this, the recommended treatment of women with hormone receptor–positive (HR positive), HER2-negative breast cancer has historically been similar for both groups.
Results from an interim analysis of the MONALEESA-7 (ClinicalTrials.gov identifier: NCT02278120)33 trial indicate that combining the CDK4/6 inhibitor ribociclib with endocrine therapy provides an overall survival advantage for pre and perimenopausal women with advanced HR-positive, HER2-negative breast cancer, compared with standard endocrine therapy plus placebo. The trial enrolled 335 patients, and the estimated overall survival with ribociclib at 42 months was 70.2%, compared with 46% for womenwho received placebo plus standard treatment. Endocrine therapy consisted of goserelin plus either a nonsteroidal aromatase inhibitor (ie, letrozole or anastrozole) or tamoxifen. Overall survival was a prespecified secondary endpoint of this trial (progression-free survival was also improved and had been reported previously). Adverse events with ribociclib were similar to those seen in previous studies. Neutropenia was greater for patients receiving ribociclib (63.5% v 4.5%). Hepatobiliary toxic effects (11% and 6.8%, respectively) and abnormal heart rhythm (in 1.8% and 1.2%, respectively) were also greater for patients who received ribociclib.
While the role of therapies like ribociclib in breast cancer continues to evolve, MONALEESA-7 shows a clear overall survival benefit in pre- or perimenopausal women with HR positive, HER2-negative advanced breast cancer. These findings represent an important step forward for the treatment of women with this disease.
More Highly Targeted Drug Combinations Work Together to Improve the Survival for Prostate and Kidney Cancer
The efficacy of single-agent targeted and immune therapies has led researchers to investigate potentially more powerful combinations. The hope is that these multipronged approaches will further extend survival without increasing toxicity. Two studies in RCC published this year have advanced the case for combining immunotherapies with a type of targeted therapy called tyrosine kinase inhibitors in the first-line treatment setting. In the KEYNOTE-426 trial (ClinicalTrials.gov identifier: NCT02853331),34 investigators demonstrated that treatment with the combination of axitinib and pembrolizumab resulted in significantly longer survival and better response than with standard sunitinib alone in patients with previously untreated metastatic RCC. Axitinib is a tyrosine kinase inhibitor that works by blocking the growth of blood vessels, and thus the flow of blood, to a tumor. Pembrolizumab is a PD-1 targeted immunotherapy, called an immune checkpoint inhibitor, that works by helping the immune system identify and target cancer cells. Axitinib is better tolerated than sunitinib, making it an attractive addition to pembrolizumab.
In the study, the estimated 18-month overall survival was 82.3% and 72.1%, respectively, for the combination of axitinib and pembrolizumab compared with sunitinib (standard therapy). Progression-free survival was also greater for the combination therapy—15.1 v 11.1 months. Grade 3 or greater adverse events from any cause were 75.8% for combination therapy and 70.6% for sunitinib.
In a second trial, called JAVELIN Renal 101 (ClinicalTrials.gov identifier: NCT02684006),35 investigators demonstrated longer progression-free survival with the combination of avelumab (a PD-L1 targeted immunotherapy) and axitinib compared with standard sunitinib therapy in patients with advanced, newly diagnosed RCC. The median progression-free survival was 13.8 months for the combination v 7.2 months for sunitinib. The rate of any adverse events and those grade 3 or greater were comparable in the two groups (71%).
In prostate cancer, new research has shown that combining different types of drugs that target the androgen pathway is effective in treating men newly diagnosed with metastatic prostate cancer. In the ENZAMET trial (ClinicalTrials.gov identifier: NCT02446405),36 investigators demonstrated that combining the targeted androgen receptor inhibitor enzalutamide with standard androgen suppression improved progression-free survival and overall survival over less-specific targeted androgen-receptor therapy (standard nonsteroidal antiandrogen drugs bicalutamide, nilutamide, or flutamide).
Prostate cancer is stimulated to grow by high levels of androgens. The cancer, however, can become resistant, with the ability to survive with even a small amount of androgen. Enzalutamide works by blocking androgen from supporting tumor growth in a more specific way than standard hormone therapies. Overall survival at 3 years was estimated to be 80% for the enzalutamide group, compared with 72% for the standard therapy group. Clinical progression-free survival was 67% and 37% at 3 years, respectively. Serious adverse events were more common with enzalutamide; 1,125 men were randomly assigned, and 563 received enzalutamide; seven patients experienced seizures, and six discontinued treatment as a result.
These studies demonstrate progress in data needed to balance efficacy and toxicity and to gain a more favorable efficacy profile. In April 2019, the FDA approved pembrolizumab plus axitinib for the first-line treatment of patients with advanced RCC.37 Approval was based on KEYNOTE-426. In May 2019, the FDA approved avelumab plus axitinib for first-line treatment of patients with advanced RCC.38 Approval was based on JAVELIN Renal 101. Also in 2019, the FDA granted priority review to enzalutamide for the treatment of men with metastatic hormone-sensitive prostate cancer. Taken together, these trials are changing standard first-line therapy for advanced stage kidney and prostate cancer.
Addition of Lomustine to Temozolomide Improves Survival in Glioblastoma
Glioblastoma (also known as glioblastoma multiforme, or GBM) is a fast-growing brain tumor. Glioblastoma is challenging to treat for several reasons: many drugs do not cross into the brain easily, or prove toxic to other brain tissues; glioblastomas are generally resistant to conventional therapies; surgery can be difficult depending on the location of the tumor in the brain; and radiation therapy can damage adjacent tissue.
Since its approval in 2005,39 temozolomide has been a mainstay of treatment of adults with newly diagnosed glioblastoma, used concurrently with radiotherapy and also as maintenance therapy after radiotherapy. Temozolomide is especially effective at extending survival among patients with tumors that have a particular marker (methylation of the MGMT gene promoter) associated with treatment sensitivity.
Lomustine (CCNU) is an alkylating anticancer drug that alters tumor DNA to prevent replication and hasten cell death. Lomustine is also able to cross the blood-brain barrier, making it an attractive addition to temozolomide for glioblastoma treatment. Based on preclinical research and positive, small phase II study results, researchers conducted an open-label randomized phase III trial to evaluate the combination of lomustine and temozolomide in patients with newly diagnosed glioblastoma positive for methylated MGMT gene promoter.
In the CeTeG/NOA-09 trial (ClinicalTrials.gov identifier: NCT01149109),40 129 patients were randomly assigned to receive temozolomide with radiation or temozolomide plus lomustine with radiation. Patients who received the combination treatment had a significantly improved median overall survival compared with those who received only temozolomide—48.1 months compared with 31.4 months, respectively. There was slightly more toxicity with lomustine/ temozolomide, mainly related to myelosuppression. Although these results are exciting, this was a small study, and larger studies will be needed to confirm these results and weigh the benefit of this combination therapy against the increased toxicity.
In First Major Advance in Decades, Immune Checkpoint Inhibitor Prolongs Survival in Extensive Small-Cell Lung Cancer When Added to First-Line Chemotherapy
In extensive-stage small-cell lung cancer (SCLC), where disease has spread throughout both lungs, to the lymph nodes on the opposite side of the chest from the primary tumor, or to other parts of the body, current treatment relies on platinum-based chemotherapy and the drug etoposide. Etoposide was approved in the early 1980s,41 and there have been no major advances in the treatment of extensive stage SCLC since that time. A number of phase III trials have been conducted to evaluate other chemotherapy regimens or the addition of targeted therapies. None of these strategies, however, have been successful.
The IMpower 133 study (ClinicalTrials.gov identifier: NCT02763579)42 was a double-blinded phase III trial assessing the immunotherapy atezolizumab in combination with chemotherapy. Atezolizumab is an anti–PD-L1 monoclonal antibody. For the study, 403 patients with extensive-stage SCLC received carboplatin and etoposide chemotherapy with or without atezolizumab. Patients who received atezolizumab had significantly longer overall survival and progression-free survival—12.3 and 5.2 months, respectively—compared with carboplatin and etoposide alone (10.3 months and 4.3 months). In general, adverse events were comparable for the two treatment strategies, though immune-related adverse events (eg, rash and hyperthyroidism) were more common among patients who received atezolizumab. The findings led to FDA approval of atezolizumab in combination with chemotherapy in March 2019.43 The combination therapy has become the standard of care for extensive-stage SCLC in the United States.
Double and Triple Combinations of Targeted Therapy for BRAF-Mutated Metastatic Colorectal Cancer Improves Overall Survival
Approximately 8% to 15% of metastatic colorectal cancers (CRCs) carry the BRAF V600E mutation, which is associated with worse survival and poorer response to standard therapy.44,45 However, single drugs aimed at inhibiting BRAF have not been effective against BRAF-mutated CRCs.46 Inhibition of the BRAF pathway results in upregulation of the EGFR pathway, which results in lack of effectiveness. Adding the EGFR inhibitor blocks the upregulated pathway so that the treatment becomes effective—with both the EGFR and BRAF portions of the pathway being blocked. Preclinical data suggest inhibition of EGFR and/or MEK is needed to inhibit the BRAF pathway in CRC.47 Therefore, multidrug therapy has raised interest as a potentially more potent therapy for these cancers.
Following a pilot study, the BEACON CRC trial (ClinicalTrials.gov identifier: NCT02928224) was initiated to compare either encorafenib (BRAF inhibitor) plus cetuximab or encorafenib plus cetuximab and binimetinib (MEK inhibitor) to the investigator’s choice of cetuximab plus either irinotecan or FOLFIRI (5-fluorouracil, leucovorin, irinotecan).48-50 More than 600 patients with BRAF V600E–mutant metastatic colorectal cancer were randomly assigned to one of the three arms. Median overall survival was significantly improved for both the two-drug (8.4 months) and three-drug (9 months) arms, compared with 5.4 months for standard therapy. In addition, the confirmed objective response rate was highest with the trio, at 26%, compared with 2% for the control arm.
Given the poor prognosis of BRAF-mutated CRC, these results are practice changing and represent a significant advance for these patients. The findings suggest that it may be important for patients with metastatic CRC to be tested for BRAF mutations to guide therapy. While the study was not powered to compare the triple and double regimens, future analyses will explore this.
Combination Regimen Improves Survival for Two Common Types of B-Cell Non-Hodgkin Lymphoma
Indolent B-cell non-Hodgkin lymphomas (NHLs), cancers of the immune system, are typically slow growing, with few to no symptoms; however, they may transform into more aggressive lymphomas and require treatment when they grow beyond a certain size or compromise vital organ function. Indolent lymphomas are not curable with conventional therapies; thus, the goal in treating patients is to maximize response while minimizing treatment-related toxicity. The most common indolent types of NHL are follicular lymphoma and marginal zone lymphoma.51 In 2019, the FDA approved the first combination treatment regimen that does not include chemotherapy—rituximab plus lenalidomide—for patients with these types of NHL.52
Rituximab is an immunotherapy that targets B cells for destruction by the immune system. Lenalidomide is a type of drug that modifies the immune system and is used to treat multiple myeloma. It works by directly inducing tumor cell death, and it works indirectly to inhibit the bone marrow, which is responsible for the production of blood and immune cells.
The AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001)53 provided key data on the efficacy and safety of the combination for the treatment of patients with follicular lymphoma and marginal zone lymphoma that has relapsed or not responded to prior treatment. AUGMENT was a phase III, randomized placebo-controlled trial of rituximab with or without lenalidomide involving 358 patients with indolent B-cell NHL with a primary endpoint of progression-free survival. Progression-free survival was significantly better with the combination of lenalidomide and rituximab compared with rituximab alone—39.4 v 14.1 months, respectively. The therapy was well tolerated, although infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with the combination regimen. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were also higher with lenalidomide plus rituximab.
“We are now learning every day about how everyone’s cancer is as individual as they are. Twenty years ago, for many patients there was only one treatment available. Today, thanks to the gains we’ve made in precision medicine and other areas, that’s no longer true.” —Don S. Dizon, MD, FACP, FASCO
Dr. Dizon is an oncologist at the Lifespan Cancer Institute at Rhode Island Hospital in Providence, Rhode Island, and is featured in ASCO's I Live to Conquer Cancer Campaign. Learn more about why Dr. Dizon lives to conquer cancer.
Drug Targeting DNA Repair Delays Disease Progression in Women With Advanced Ovarian Cancer
PARP (poly [ADP-ribose] polymerase) inhibitors, such asthe drug olaparib, promote cancer cell death by interfering with DNA replication in cancers that have faulty DNA damage repair genes as a result of genetic mutations (ie, BRCA 1 and 2). When BRCA 1 and/or BRCA 2 genes are mutated—and don’t repair damaged DNA—PARP enzymes can repair DNA enough to allow cancers to live and multiply. Olaparib blocks PARP. As a result, DNA damage is not repaired, and cancer cell death is accelerated.
Standard treatment of newly diagnosed advanced ovarian cancer consists of cytoreductive surgery along with platinum-based chemotherapy.54 While initially effective, approximately 70% of patients relapse within 3 years.55 Recurrent disease is often incurable.
In the phase III SOLO1 trial (ClinicalTrials.gov identifier: NCT01844986),56 researchers found that maintenance treatment with olaparib improved progression-free survival compared with placebo for women with advanced (stage III or IV) BRCA 1/2 mutated ovarian cancer. PARP inhibitors like olaparib promote cancer cell death by impairing DNA replication in cancers that have faulty DNA repair genes (ie, BRCA 1 and 2).
In this trial, patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer were randomly assigned to receive either olaparib or placebo until disease progression. All 391 patients included in the study responded to platinum-based treatment following at least an attempt at surgery. Patients who received olaparib were 70% less likely to experience either cancer progression or death compared with those who received placebo after a median follow-up of 42 months. A similar advantage was still seen at 3 years. The most common adverse events were grade 1 or2 and included nausea, fatigue, vomiting, and diarrhea. Serious adverse events were more likely among patients who received olaparib—21% v 12% for the placebo group, with anemia being the most common.
These findings led to FDA approval of olaparib for this indication and have substantially changed practice for women with advanced (stage III or IV) ovarian cancer who have BRCA 1/2 mutations.57
Bladder Cancer Survival Improves With Targeted Therapies
Advances were also seen with molecular therapies this year. While platinum-based combination therapy approaches are standard of care for patients with bladder cancer, many cancers do not respond. In addition, patients with poor renal function are often unable to safely receive cisplatin chemotherapy, leaving them with even fewer treatment options. Data on two promising new molecular targets (FGFR2/3 and Nectin 4) were presented at the 2019 ASCO Annual Meeting.
One study (JNJ-42756493, ClinicalTrials.gov identifier: NCT02365597)58 examined erdafitinib (Balversa) for the treatment of locally advanced or metastatic urothelial cancer. Erdafitinib is a pan inhibitor of human fibroblast growth factor receptors (FGFR) that works to reduce blood flow to a tumor, causing it to shrink and die. The study reported treatment of 99 patients who previously received at least two courses of therapy, including 22 patients who had received immunotherapy. The overall response rate to erdafitinib was 40% overall and 59% for the patients who had undergone previous immunotherapy. Although there were no treatment-related deaths, 13% of patients discontinued treatment due to adverse events. In April 2019, the FDA granted accelerated approval to erdafitinib for the treatment of patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.59
In a second study, EV-201 (ClinicalTrials.gov identifier: NCT03219333),60 125 patients with locally advanced or metastatic urothelial bladder cancer received enfortumab vedotin after checkpoint inhibitors and platinum-based chemotherapy failed to control the disease. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which plays a role in helping cancer cells stick together to form tumors. The researchers reported on the first cohort, and the overall response rate with enfortumab vedotin was 42%. Taken together, these two studies demonstrate a completely new direction in advanced urothelial cancer, moving from multi-treatment chemotherapy, to the incorporation of checkpoint inhibition, and now to molecular targeting
Immunotherapies and Tyrosine Kinase Inhibitor Approved for the Treatment of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) incidence is growing in the United States. It is also one of the most common cancer types diagnosed each year worldwide.61 More than a decade ago, sorafenib became the first-approved targeted therapy against HCC.62 Progress was then limited until the past year, when several positive studies emerged that led to FDA approvals of three new drugs for this cancer—pembrolizumab, cabozantinib, and ramucirumab.
The KEYNOTE-224 (ClinicalTrials.gov identifier: NCT02702414) trial demonstrated that pembrolizumab is promising for the treatment of advanced HCC.63 In this nonrandomized open label study, 104 patients with HCC that had progressed after sorafenib or who were resistant to the therapy received pembrolizumab. Eighteen patients (17%) had an objective response (one complete, 17 partial), and forty-six patients (44%) had stable disease. Almost three-quarters (73%) of patients had adverse events, with nearly a quarter of patients (24%) having a grade 3 event. In November 2018, the FDA granted accelerated approval to pembrolizumab for patients who have been previously treated with sorafenib.64
Cabozantinib showed a survival advantage over placebo in the CELESTIAL trial of previously treated patients with advanced HCC (ClinicalTrials.gov identifier: NCT01908426).65 The phase III study included 707 patients who received sorafenib and had disease progression after at least one systemic therapy; the patients were randomly assigned to receive cabozantinib or placebo. Median overall survival was 10.2 months with cabozantinib v 8 months with placebo. Median progression-free survival was 5.2 and 1.9 months, respectively. Grade 3 or 4 adverse events were more common among patients who received cabozantinib—68% v 36%, respectively. The most common high-grade adverse events included hand-foot syndrome (redness, swelling, and pain on the palms and/or the soles of the feet) and hypertension. In January 2019, cabozantinib was approved for patients with advanced HCC who have been previously treated with sorafenib.66
In patients with HCC, an elevated concentration of AFP has been associated with poor prognosis. In the REACH-2 trial (ClinicalTrials.gov identifier: NCT02435433),67 patients with HCC and elevated AFP were randomly assigned to receive ramucirumab or placebo. The patients who received ramucirumab had longer median overall survival and progression-free survival than those who received placebo—8.5 v 7.3 months (overall survival) and 2.8 v 1.6 months (progression-free survival), respectively. Grade 3 or worse treatment-emergent adverse events were more common in those receiving ramucirumab than placebo. The most common were hypertension (elevated blood pressure), hyponatremia (low sodium level), and increased aspartate aminotransferase (a measure of liver damage). In May 2019, ramucirumab was approved as a single agent in patients with an AFP of at least 400 ng/mL and who have been previously treated with sorafenib.68
Immunotherapy Makes Inroads in Head and Neck Cancer
Following the initial approval of two immunotherapies (nivolumab and pembrolizumab) for the treatment of patients with recurrent and/or metastatic head and neck cancer that persists after platinum-based therapy, significant interest has arisen to define additional patient populations that may benefit. Two studies represent the first that will help to define the optimal treatment approach for these patients.
The KEYNOTE 040 (ClinicalTrials.gov identifier: NCT02252042)69 open-label, phase III trial included patients with head and neck squamous cell carcinoma. The trial enrolled patients with cancer that progressed during or after platinum containing treatment of recurrent or metastatic disease (or both) or that recurred or progressed within 3-6 months of previous multimodality treatment containing platinum for locally advanced disease. Patients were randomly assigned to receive pembrolizumab (247 patients) or the investigator’s choice of standard doses of methotrexate, docetaxel, or cetuximab (standard of care, 248 patients). Median overall survival was 8.4 months with pembrolizumab and 6.9 months with standard of care. Grade 3 or worse treatment-related adverse events occurred in fewer patients treated with pembrolizumab compared with standard of care. The most common treatment-related AE with pembrolizumab was hypothyroidism; with standard care it was fatigue.
In the KEYNOTE-048 trial (ClinicalTrials.gov identifier: NCT02358031),70 patients with recurrent or metastatic squamous cell cancer of the head and neck were randomly assigned to receive pembrolizumab alone or with platinum-based chemotherapy, or cetuximab plus platinum-based chemotherapy. With all patients included in the analysis, pembrolizumab did not significantly improve overall survival over cetuximab/chemotherapy—median overall survival was 11.5 v 10.7 months (pembrolizumab plus chemotherapy was not compared against cetuximab plus chemotherapy in this patient group). However, the median overall survival in the group of patients with higher levels of PD-L1 (a protein that helps tumors hide from the immune system) was better for those who received pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy: 14.7 months v 11 months (pembrolizumab alone was not compared with cetuximab plus chemotherapy in this group). All-cause grade 3-5 adverse event rates were 54.7% for pembrolizumab alone, 85.1% for pembrolizumab/chemotherapy, and 83.3% for cetuximab/chemotherapy.
Checkpoint Inhibitors Prolong Survival in Locally Advanced NSCLC and in Advanced Squamous NSCLC
An estimated 20% to 30% of all lung cancers are squamous NSCLC, which is associated with poorer survival than nonsquamous NSCLC.71 Treatment of these patients has been limited to platinum-based chemotherapy. In addition, there have been no major advances in the treatment of unresectable stage III disease since the confirmation that concurrent chemotherapy and radiation improve survival compared with sequential therapy.72
Two phase III randomized trials have suggested that these therapies are effective and safe for patients with NSCLC. In the phase III PACIFIC trial (ClinicalTrials.gov identifier: NCT02125461),73 the addition of the PD-L1–targeted drug durvalumab significantly prolonged overall survival and progression-free survival, as compared with placebo. Patients in this study had stage III, unresectable NSCLC and did not have disease progression after concurrent chemoradiotherapy. At 2 years of follow-up, median overall survival in the 183 patients who received durvalumab was 66.3%, compared with 55.6% in the 116 patients in the placebo group. Median progression-free survival was 17.2 months for patients receiving durvalumab, compared with 5.6 months for those receiving placebo. Serious adverse events were more common for patients in the durvalumab group—29.1% v 23.1% in the placebo group. Following FDA approval, longer follow-up data showed improved overall survival with the addition of durvalumab. At an update presented at the 2019 ASCO Annual Meeting, researchers reported that at 3 years the overall survival was 57% in the durvalumab arm compared with 43.5% in the placebo arm.
The KEYNOTE 407 trial (ClinicalTrials.gov identifier: NCT02775435)74 examined the addition of the PD-1 targeted agent pembrolizumab to carboplatin-based chemotherapy (with paclitaxel or nab-paclitaxel) in patients newly diagnosed with advanced squamous NSCLC. Both overall survival (15. 9 months v 11.3 months) and progression-free survival (6.4 v 4.8 months) were longer in patients who received pembrolizumab (278 patients) compared with placebo (271 patients). Adverse events of grade 3 or greater occurred in 69.8% of patients receiving pembrolizumab in combination with chemotherapy compared with 68.2% of patients receiving placebo and chemotherapy. Anemia, alopecia, and neutropenia were the most common adverse events in both groups. The results of this study established this regimen as the new standard of care for patients with advanced squamous NSCLC not previously treated.
Anti-CD47 Plus Rituximab Shows Initial Promise in Relapsed/Resistant Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma originates in the body’s lymph system and includes several types (eg, diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma are two common types). For patients with DLBCL that becomes resistant to treatment with rituximab, the prognosis is poor, with a median survival of 6 months.75 For patients with follicular lymphoma with disease that has progressed in less than 2 years after diagnosis or is resistant to combination regimens with rituximab, survival is 50%.76,77
CD47 is a protein that protects certain cells from the immune system—a “don’t eat me” signal of sorts. While many cells have some CD47 on their surfaces, tumor cells have lots of it. This helps tumors avoid destruction, allowing them to grow and spread. High amounts of CD47 indicate poor prognosis. An investigational drug known as 5F9 (short for Hu5F9-G4) is thought to block CD47, giving the immune system a chance to identify and destroy cancer cells. Preclinical research suggests that adding 5F9 to rituximab (a tumor-fighting monoclonal antibody) may have a synergistic effect (stronger effect than just the two treatments combined).
A first-in-human, phase Ib study (ClinicalTrials.gov identifier: NCT02953509)78 published in 2019 assessed both the safety and efficacy of different doses of 5F9 in 22 patients with relapsed or resistant DLBCL or follicular lymphoma. Patients were randomly assigned to receive one of three dosages of 5F9 in combination with rituximab.
The combination showed promising preliminary efficacy: after a median of 22 weeks, half of patients had objective response (shrinkage in the tumors), including 36% with complete response. Responses were ongoing for 91% of patients. The response rates were higher in follicular lymphoma (70%) compared with DLBCL (40%). Adverse events were predominantly grades 1 and 2 headache, anemia, and infusion-related reactions. While the study was small, the results warrant larger and longer studies.
Based on these data, the combination of lenalidomide and rituximab was FDA approved for relapsed indolent B-cell NHL.79 Ongoing studies are exploring this combination in earlier lines of relapse and in combination with other novel and targeted therapies for patients with multiply relapsed disease. The study was funded, in part, by the NIH.
Lower Intensity Methotrexate Treatment of Children, Adolescents, and Young Adults With T-ALL Results in High Cure Rates
Acute lymphoblastic leukemia (ALL) is a malignancy that affects a category of blood cells known as lymphocytes. ALL affects two types of lymphocytes: B cells and T cells. B cells protect the body by making antibodies against invaders, and T cells can directly attack cancer cells as well as help B cells do their job.
T-cell ALL (T-ALL) accounts for about 15% of pediatric patients with ALL, and it is more common in older adolescents and African American children and adolescents. Unfortunately, T-ALL is associated with shorter event-free survival (the time from treatment to disease progression or the development of certain symptoms) and overall survival compared with the more common B-cell disease.
Methotrexate is an anticancer drug that has been a mainstay of treatment of ALL for decades. Nevertheless, the most effective and least toxic schedule and dosing of methotrexate for T-ALL in pediatric patients has been unclear.
Two different approaches are commonly used to reach therapeutic levels (levels high enough to achieve effective treatment) of methotrexate in young patients with ALL; however, these have not been evaluated in the treatment of T-ALL. The first strategy is called Capizzi-style methotrexate (C-methotrexate, or C-MTX). It involves starting with a lower dose of methotrexate and increasing it over time. C-MTX is often coupled with PEG-asparaginase, another drug used to treat ALL. With high-dose methotrexate (HDMTX) therapy, patients receive the same high dose of methotrexate throughout treatment. HDMTX is often associated with kidney damage and other adverse events. For this reason, leucovorin (folinic acid) is started after treatment with HDMTX, to help mitigate toxicity.
The toxicity of HDMTX and the success seen with C-MTX in other cancers (including B-ALL) led researchers to examine which one was optimal in T-ALL. In the phase III AALL0434 trial (ClinicalTrials.gov identifier: NCT00408005)80 led by the Children’s Oncology Group, 1,000 patients were randomly assigned to receive C-MTX or HDMTX (with or without nelarabine). C-MTX treatment was superior in terms of 5-year disease-free survival and overall survival. Disease free survival was 91.5% and 85.3% for C-MTX and HDMTX, respectively. Overall survival was 93.7% and 89.4%. Patients assigned to C-MTX had 32 relapses, six involving the central nervous system. Those assigned to HDMTX had 59 relapses, 23 involving the central nervous system. Grade 3 and 4 adverse events during an interim maintenance phase were comparable and included febrile neutropenia and seizures. It is important to note, however, that cranial radiation was administered earlier for patients receiving C-MTX than for those receiving HDMTX, which could have influenced the outcomes.
Thus, the federally funded AALL0434 trial established that chemotherapy with C-MTX is superior to HDMTX for T-ALL as administered in the protocol. Furthermore, the trial showed the best outcomes ever reported for children and adolescents with T-ALL. It showed a 5-year disease-free survival rate of 91.5% and overall survival rate of 93.7%. In comparison, the historical overall survival rate for T-ALL was approximately 81% based on earlier clinical trials in this patient population.81 This study was funded, in part, by the NCI.
Children With Resected Hepatoblastoma Can Be Cured With Minimal Adjuvant Chemotherapy
Hepatoblastoma is a type of liver cancer composed of cells that resemble embryonic tissue and is the most common type of childhood liver malignancy. Treatment requires surgical resection; however, only about a third of newly diagnosed patients have resectable disease at diagnosis.82 These patients typically receive four to six cycles of cisplatin-based adjuvant chemotherapy, which carries increased toxicity.83 New strategies are needed to decrease long-term effects for children with this cancer, particularly hearing damage due to cisplatin.
The phase III AHEP0731 study (ClinicalTrials.gov identifier: NCT00980460)84 enrolled children with hepatoblastoma in four risk groups based on several risk factors at diagnosis. Results from children with the lowest risk were reported. Children in this risk group were treated with complete resection at diagnosis and maintenance therapy consisting of only two cycles of adjuvant cisplatin-based chemotherapy. Eligible patients were younger than 21 years and had histologically confirmed stage I or II hepatoblastoma (excluding those with 100% pure fetal stage I or small-cell undifferentiated histology). Event-free survival was 92% at 4 years and 88% at 5 years, based on 49 evaluable patients. The most common grade 3 to 4 adverse events included febrile neutropenia (14%), decreased neutrophil count (6%), infections (8%), and diarrhea (8%). Ototoxicity (hearing damage) occurred in one patient. One patient, out of the three who relapsed in this cohort, died as a result of the cancer. There were no treatment-related deaths. This study was funded by the NCI.
Promising Results of the Use of the MEK Inhibitor Selumetinib for the Treatment of Children and Adolescents With Refractory Low-Grade Gliomas
Pediatric low-grade glioma is the most common central nervous system tumor in children. While overall survival is generally high, the disease often recurs. No single treatment is universally accepted for these patients. However, standard cytotoxic chemotherapies and radiation therapy are commonly used. In the past 15 years, though, research has shown that nearly all pediatric low-grade gliomas have alterations that activate the RAS-MAP kinase pathway. Selumetinib is part of a new class of drugs called MEK inhibitors that block this process.
The Pediatric Brain Tumor Consortium conducted a phase II trial of selumetinib (ClinicalTrials.gov identifier: NCT01089101)85 in children age 3 to 21 years who had varying forms of recurrent, refractory, or progressive pediatric low-grade glioma. The trial was composed of six groups, or strata. This publication included data for strata 1 and 3. The first stratum included 25 patients with a type of glioma called grade I pilocytic astrocytoma. This cancer commonly has mutations that should make it susceptible to selumetinib. The third stratum included 25 patients either with imaging characteristics suggestive of a pediatric low-grade glioma or biopsy-proven low-grade glioma and a clinical or genetic diagnosis of neurofibromatosis type 1. Patients in both strata received 28-day courses of oral selumetinib for up to 26 cycles. More than one-third (36%) of patients in stratum 1 had a partial response; nine had stable disease, and seven had progressive disease. However, more than half of these patients (56%) had progression (nine during treatment and five after completion). All patients in stratum 3 had some evidence of tumor shrinkage with selumetinib, including 10 (40%) partial responses. One patient experienced disease progression while on therapy; seven had progression after therapy completion. Most toxic effects were moderate, although 36% of patients required a dose reduction of selumetinib. The trial is ongoing, and data for other strata are not yet mature. The study was funded by the NCI.
Internet-Based Cognitive Behavioral Therapy Improves Treatment-Induced Menopausal Symptoms in Women With Breast Cancer
Adjuvant breast cancer treatments, including chemotherapy, surgery, and/or endocrine therapy, often cause bothersome side effects that severely alter patients’ quality of life. For young women treated for breast cancer, this can mean menopause-like symptoms, with hot flashes and night sweats among the most common. Eighty percent of such women in one study reported hot flashes, and 72% reported night sweats.86 Women can also experience problems with sleep quality, sexual functioning, and psychological distress. It has also been shown that these symptoms can lead some women to reduce or even to discontinue endocrine therapy.87
Effective treatment of these symptoms is rather limited, and many come with side effects. New research, however, suggests that cognitive behavioral therapy may be helpful to reduce the burden of hot flashes and night sweats in patients with breast cancer.88
In a study (ClinicalTrials.gov identifier: NCT02672189)90 published this year, researchers examined the efficacy of a 6-week internet-based CBT program, either self-directed or with support from a therapist, compared with being on a waiting list for help with symptoms. The randomized controlled trial included 254 women no older than 50 years at the time of breast cancer diagnosis who had undergone chemotherapy and/or oophorectomy (surgery to remove one or both ovaries) and/or endocrine treatment. The women were experiencing treatment-induced bothersome hot flashes or night sweats. At 10 weeks, both groups using the internet-based CBT reported significant improvements in hot flashes and night sweats (the primary outcome) and sleep quality compared with women in the waitlist group. Improvements were also seen in frequency of night sweats and menopausal symptoms overall for women in the therapist-guided group. At 24 weeks, the self-guided group reported improved overall menopausal symptoms and the therapist-guided group continued to report improved hot flashes and night sweats. Both CBT groups reported decreased frequency of night sweats with longer follow-up.
The findings demonstrate that a self-guided internet-based CBT program can significantly alleviate menopausal symptoms for women with breast cancer. If validated in larger studies, internet-based CBT could provide an accessible, effective complement to medications.
The number of new FDA approvals in oncology continues at a rapid pace. From November 2018 through October 2019, the FDA approved 43 new cancer therapies or new indications of cancer therapies (Appendix Table A1, online only).
Our understanding of the biology of cancer continues to grow rapidly, leading to new types of targeted treatments and novel therapeutic approaches. In the past year, treatments were combined in new ways, optimal dosing and scheduling were identified for existing treatments, and adverse events were reduced. Researchers also identified groups of patients more likely to benefit from specific treatments and made strides in surgery and radiotherapy.