After witnessing 10 years of breakthroughs across the spectrum of cancer care, oncology experts are looking ahead as a new decade begins to capitalize on those wide-ranging therapeutic and diagnostic gains.
After witnessing 10 years of breakthroughs across the spectrum of cancer care, oncology experts are looking ahead as a new decade begins to capitalize on those wide-ranging therapeutic and diagnostic gains. To find out what might be on the horizon for 2020, OncologyLive® reached out to prominent leaders in the field. Their overall take: Developments in unraveling resistance to immune checkpoint inhibitor (ICI) therapy and molecular diagnostics will be the most active areas of research in 2020.
The experts made their observations against a backdrop of remarkable, practice-changing advancements. Since 2010, major oncology trends include the broad adoption of ICIs, the development of new classes of agents targeting molecular drivers of malignancies, and the introduction of genetically modified T-cell therapies.
In 2019 alone, the FDA approved the first PD-1/PD-L1—target-ing immunotherapy, atezolizumab (Tecentriq), for patients with triple-negative breast cancer (TNBC); the first targeted therapy, erdafitinib (Balversa), for urothelial carcinoma; and 2 new therapies for hepatocellular carcinoma, ramucirumab (Cyramza) and cabozantinib (Cabometyx).1
Edward S. Kim, MD
Edward S. Kim, MD
Levine Cancer Institute
In 2005, Edward S. Kim, MD, and colleagues launched what was then a revolutionary type of clinical study: an umbrella trial in which the tumors of patients with chemorefractory non—small cell lung cancer (NSCLC) would be prospectively biopsied, with participants assigned to a targeted therapy depending on molecular analysis. The initial BATTLE trial, which led to a series of studies, was a proving ground for the use of real-time biopsies in an era that predated the development of companion diagnostics.2,3
Today, the BATTLE trials’ approach to precision medicine is such an accepted part of oncology practice that some aspects no longer spark debate, notes Kim, who chairs the Department of Solid Tumor Oncology at Levine Cancer Institute at Atrium Health in Charlotte, North Carolina. “I love the fact that there wasn’t much of a discussion for the last several years about what type of biopsy should you get,” he said in an interview. “I think now we understand the importance of getting adequate tissue and that the biomarker profile or the genomic profile is as important as the histologic diagnosis.”
One emphasis will be on expanding the criteria for clinical trial enrollment so that more patients qualify, Kim said. He is working with the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research to promote broader eligibility rules.
At the 2019 ASCO Annual Meeting, Kim and colleagues reported on an analysis of the impact that less restrictive criteria for primary cancers, brain metastases, and renal function would have on 10,500 patients with advanced NSCLC whose records were drawn from ASCO’s CancerLinQ Discovery database. They found that 98.5% of patients would be accepted for NSCLC trials under the expanded criteria versus 52.3% under traditional criteria.4
In terms of therapeutics, Kim mentioned 2 trends on his radar not just for NSCLC but also for other solid cancers: earlier use of emerging agents and greater efforts to develop strategies for patients who relapse after receiving an ICI. “The novel and cutting-edge treatments that we have—the biologic treatments, the targeted treatments, the immunotherapy treatments—are making their way down to earlier settings in curable patients,” he said. “So, [the goal is] not only impacting the lives of patients who have incurable disease but [also]—where you can really move the curve—affecting people who have curable disease and, in fact, help them live longer."
At the same time, Kim said, investigators will be focusing on next steps for people who stop responding to ICIs, including novel single agents and combinations. “Immunoresistance and overcoming it is going to be the next big frontier,” he said. “A lot of people are getting treated on them now, but when they stop working, we don’t know what to give.”
Lisa A. Carey, MD
Lisa A. Carey, MD
University of North Carolina Lineberger Comprehensive Cancer Center
An internationally recognized investigator into the molecular subtypes of breast cancer, Lisa A. Carey, MD, anticipates near-term advancements to flow from data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS).
Findings from the KEYNOTE-522 trial could add a new immune checkpoint inhibitor to the armamentarium for TNBC, and results from ATEMPT demonstrate the increasing viability of rational de-escalation of treatment in HER2-positive disease, according to Carey. She is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
In previously reported results from the phase III KEYNOTE-522 (NCT03036488) study, patients who received neoadjuvant pembrolizumab (Keytruda), a PD-1 inhibitor, plus chemotherapy had a significantly higher pathological complete response (pCR) rate compared with those who received chemotherapy alone (64.8% vs 51.2%, respectively; CI, 5.4-21.8).5
In updated data from SABCS, the pCR rate among patients whose cancers had spread to the lymph node was 64.8% in the pembrolizumab arm versus 44.1% in the chemotherapy-alone group. High rates of pCR were also observed in patients with stage III disease.6
The combination has demonstrated efficacy regardless of PD-L1 status, Carey said. If the regimen proves to have a significant effect on event-free survival when the data mature, it could have a major impact for patients. “That would bring a new checkpoint inhibitor into the curative intent arena,” she said. “That’s going to become clearer in the next year or 2…if in the not-too-distant future we know whether or not we significantly alter outcomes by incorporating an immune checkpoint inhibitor early in TNBC.”
In March 2019, the FDA approved atezolizumab in combination with nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.
In the phase II ATEMPT Trial (NCT01853748), investigators assessed T-DM1 (ado-trastuzumab emtansine; Kadcyla) versus trastuzumab (Herceptin) plus paclitaxel for patients with early-stage, node-negative HER2-positive breast cancer.7 Carey described the experimental regimen as “doubling down on the idea of de-escalating therapy.” This patient population formerly had a very poor prognosis. Carey said aggressive treatment has improved cure rates but requires a lot of medication administered over 1 to 2 years, with the attendant adverse events.
The APT study (NCT00542451) assessed paclitaxel/trastuzumab in patients with node-negative, HER2-positive breast cancer. Seven-year follow-up data published in 2019 showed a disease-free survival rate of 93.3% and an overall survival (OS) rate of 95.0%.8 ATEMPT will determine if a regimen that omits the chemotherapy component can induce similarly good outcomes.
Carey said she doesn’t think positive results from ATEMPT will be enough to support FDA approval for T-DM1 in this indication, but, after APT, it would be the second trial suggesting that low clinical stage HER2-positive breast cancer could be treated with less chemotherapy. “That’s a direction we’ll be going in with the advent of these very effective anti-HER2 therapies,” she said.
Brian I. Rini, MD
Brian I. Rini, MD
Vanderbilt-Ingram Cancer Center
As in other disease settings, immunotherapy had a practice-changing impact in renal cell carcinoma (RCC), particularly metastatic disease.“In the past 12 to 24 months, the frontline treatment for metastatic kidney cancer has dramatically changed,” said Brian I. Rini, MD, an expert in urologic malignancies. At the heart of this shift: Immuno-oncology doublets have supplanted single-agent VEGF inhibitors that were commonly used to treat advanced disease.
In April 2018, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of intermediate- or poor-risk, treatment-naïve patients with advanced RCC.1 The regimen quickly became a standard of care (SOC) in this patient population, said Rini, chief of clinical trials at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.
Shortly thereafter came immunotherapy doublets with a VEGF backbone. Axitinib (Inlyta) and pembrolizumab scored approval as a first-line therapy for patients with advanced disease in April 2019. Axitinib and avelumab (Bavencio), a PD-L1 inhibitor, followed suit 1 month later, broadening the armamentarium for patients with advanced disease.1
The combinations of ipilimumab/nivolumab and axitinib/pembrolizumab have showed survival advantages and are considered SOC, Rini said. “Unless they cannot have an immune-oncology agent, the vast majority of patients should be getting one of these immunotherapy-based doublets first,” he added.
In 2020, Rini is anticipating findings from trials centered on 2 other VEGF and immuno therapeutic doublets: cabozantinib plus nivolumab and lenvatinib (Lenvima) with pembrolizumab. However, the potential impact of positive results from these studies is unclear.
Immunotherapy agents have also conferred benefit in urothelial carcinoma. Findings from the phase III IMvigor130 study (NCT02807636), presented at the European Society for Medical Oncology (ESMO) 2019 Congress, showed that the first-line combination of atezolizumab and chemotherapy led to a 1.9-month improvement in median progression-free survival (PFS) versus placebo/chemotherapy in patients with locally advanced or metastatic urothelial carcinoma.9 The immunotherapy combination did not show a statistically significant improvement in OS, but Rini said such regimens may offer advantages. “We’re just starting to see some of the frontline phase III data of trials comparing immunotherapy with chemotherapy or adding it to chemotherapy,” he said. “There are other phase III trials exploring these methods, and we’re all waiting for those data to understand how to approach patients.”
Findings from these exploratory studies will likely be released next year, he added: “There’s a lot of activity in first-line urothelial carcinoma that’s just starting to play out; there’s more coming in 2020.”
Tanios S. Bekaii-Saab, MD, FACP
Tanios S. Bekaii-Saab, MD, FACP
Several “big stories” for patients with gastrointestinal (GI) malignancies unfolded in 2019, according to Tanios S. Bekaii-Saab, MD, FACP.
In pancreas cancer, the notable development involved positive findings from the phase III POLO trial (NCT02184195) of olaparib (Lynparza) in patients with germline BRCA (gBRCA)—mutant metastatic pancreatic cancer whose disease did not progress on first-line platinum-based chemotherapy. Results showed that maintenance olaparib significantly slowed the progression of metastatic disease in patients with gBRCA mutations: The median PFS was 7.4 months with olaparib versus 3.8 months with placebo. POLO became the first phase III randomized investigation to demonstrate the feasibility of a biomarker-driven approach in advanced pancreatic cancer.10
“One of the elements of POLO that I think is transformational is a proof of principle that in a disease that tends to fall flat on targets, a specific targeted strategy will change outcomes,” said Bekaii-Saab, professor at the Mayo Clinic College of Medicine and Science and a consultant at Mayo Clinic in Phoenix, Arizona.
“I think what this study tells us is that we should continue efforts to develop PARP inhibitors in pancreas cancer, preferably in combination with formulations that selectively deliver active cytotoxic agents to tumors such as nanoliposomal irinotecan or immunotherapeutic strategies,” he added.
Studies into the synergistic potential of these therapies are already under way. The PARP inhibitor rucaparib (Rubraca) is being explored in combination with nanoliposomal irinotecan and “looks promising,” according to Bekaii-Saab. The role of these strategies in pancreas cancer should become clearer in the next few years, he said.
The application of targeted modalities was also key to colorectal cancer (CRC) in 2019. One of the “most exciting developments” in CRC over the past year was the identification of positive biomarkers that predict patient response to targeted therapies, according to Bekaii-Saab. “For the longest time in colon cancer, all we had was an understanding that RAS and BRAF V600E mutations were negative predictors for cetuximab [Erbitux] and panitumumab [Vectibix]; unfortunately, we didn’t have positive predictors for targeted strategies,” Bekaii-Saab said. “2019 was the year of positives for field advancement in CRC.”
BEACON CRC (NCT02928224), a phase III trial of encorafenib (Braftovi), binimetinib (Mektovi), plus cetuximab in patients with BRAF V600E—mutant CRC, moved the needle in the disease, Bekaii-Saab said. BEACON CRC demonstrated that the triplet regimen led to significantly longer median OS (9.0 vs 5.4 months; P <.0001) and higher objective response rates than standard chemotherapy (26% vs 2%), respectively.11
“BEACON CRC is a transformational study that has now changed the SOC in this subset of patients with refractory disease and likely changed its biologic behavior for about 20% to 30% of patients with BRAF V600E mutations,” Bekaii-Saab said. The trial’s impact in this disease setting will extend into 2020 with the initiation of the phase II ANCHOR-CRC study (NCT03693170), which will test the same combination in patients with treatment-naïve BRAF V600E—mutant CRC.
Patients with HER2-amplified colon cancer also benefited from the adoption of targeted therapies. “Previously, we had hints here and there from small studies that dual HER2targeting strategies such as trastuzumab and pertuzumab [Perjeta] or trastuzumab and lapatinib [Tykerb] might be advantageous for this group of patients,” Bekaii-Saab said. In these earlier studies, which consisted of 20 to 25 patients, response rates were consistently close to 30%, he said.
Presented at ESMO Congress 2019, initial data from the ongoing phase II MOUNTAINEER trial (NCT03043313) of tucatinib plus trastuzumab in patients with HER2-positive metastatic CRC showed a response rate of “close to 55%,” Bekaii-Saab said.12
Tucatinib is likely to be approved in the near future for patients in breast cancer in combination with trastusumab, given the significant and clinically relevant results of the HER2CLIMB trial (NCT02614794), he added. “In addition to the impressive clinical activity, the level of tolerability will certainly make this a very exciting regimen for patients with HER2-positive CRC. Historically and from my own experience, the combination of tucatanib and trastuzumab appears to be safer than other HER2 combinations in practice today,” Bekaii-Saab said.
“Even more exciting is the fact we’re finally moving colon cancer to subgroups identified by actionable alterations that will be matched with specific targeted regimens,” he said. The Academic and Community Cancer Research United Research Consortium is conducting the COLOMATE study (NCT03765736), in which patients with refractory metastatic CRC undergo blood-based genomic profiling.
“We’re finally moving in the right direction!” Bekaii-Saab said.