Research Recap: Hot Topics From AACR Annual Meeting 2018

Catlin Nalley

More than 22,500 attendees from over 70 countries came together in Chicago last week for the AACR Annual Meeting 2018.

During the Opening Plenary Session Elaine R. Mardis, PhD, AACR President-Elect, addressed the impact each attendee has on the ongoing progress in cancer innovation, “You represent the spectrum of cancer research and cancer-related science from population science to basic, translational, and clinical cancer research to non-biological sciences, such as mathematics, engineering, computing, and artificial intelligence, which are being increasingly integrated to our field.

“This is what makes the AACR Annual Meeting such a unique event. We created the scientific program to reflect the diversity of your research interest and chose the theme for this year’s meeting, ‘Driving Innovation in Patient Care’ to reinforce how important each of your advances in every area are to the incredible progress being made against cancer today,” she continued. “Whether you work at the bench, the bedside, or out in the community. Whether you are just launching your career or have decades of experience, your dedication to scientific excellence is paramount to reducing cancer incidence, morbidity, and mortality in the future.”

Throughout the conference, vast contributions of the cancer community were highlighted through groundbreaking research in a variety of areas, including immunotherapy, genomics, and more.


Lung Cancer & Immunotherapy

Several studies confirmed the impact immunotherapy plays on the effective treatment of lung caner patients.

KEYNOTE-189: Findings from this randomized, double-blind, phase III study showed that overall survival (OS) and progression-free survival (PFS) were significantly longer among patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer (NSCLC) who were treated with pembrolizumab plus chemotherapy compared to those who received chemotherapy alone (Abstract CT075, N Engl J Med 2018; doi:10.1056/NEJMoa1801005). 

After a median follow-up of 10.5 months, median OS was not reached in the test arm, versus 11.3 months in the control arm. “Compared with patients in the control arm, those in the test arm were 51 percent less likely to die, and those in the high PD-L1 score group were 58 percent less likely to die,” according to investigators. In the pembrolizumab arm, median PFS was 8.8 months (95% CI, 7.6-9.2) compared to 4.9 months (95% CI, 4.7-5.5) for patients in the control group.

“Adding pembrolizumab to pemetrexed and platinum induction therapy and pemetrexed maintenance therapy significantly improves OS, PFS, and ORR in patients with untreated metastatic nonsquamous NSCLC without sensitizing EGFR or ALK alterations,” noted study author Leena Gandhi, MD, PhD, Associate Professor in the Department of Medicine and Director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health, during her presentation. She concluded that the treatment “may be a new standard of care for first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression.”

CheckMate-227: This was a large, open-label, randomized phase III trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy (PT-DC) versus PT-DC in patients with stage IV or recurrent NSCLC who had not received prior treatment (Abstract CT077, N Engl J Med 2018; doi:10.1056/NEJMoa1801946).

Nivolumab plus ipilimumab significantly improved PFS compared to standard-of-care chemotherapy among newly diagnosed, advanced NSCLC patients with high tumor mutational burden (TMB, >10 mutations/Mb). “PFS at 1 year was nearly tripled, 43 percent versus 13 percent, as was the duration of response at 1 year, 68 percent and 25 percent,” according to Matthew Hellmann, MD, Assistant Attending at Memorial Sloan Kettering Cancer Center. The objective response rate was 45.3 percent in patients who received nivolumab plus ipilimumab, versus 26.9 percent in those who received chemotherapy.

“Overall, this study has the opportunity to introduce two new options for patients with NSCLC,” Hellmann said. “This first is that the study demonstrates the clinical value of nivolumab plus ipilimumab as a treatment option for patients with TMB high NSCLC.

“The combination provides a durable benefit, builds upon our progress in precision medicine thus far in lung cancer, spares the use of chemotherapy in the first-line setting, and allows the second-line an effective option to be used if needed,” he continued.

Neoadjuvant PD-1 Blockade: Researchers found that nivolumab was safe and resulted in major pathological responses in 45 percent of patients when administered prior to surgical resection of stage I-III NSCLC (Abstract CT079N Engl J Med 2018; doi:10.1056/NEJMoa1716078).

“Nine of 20 patients (45%) achieved a major pathological response defined as less than 10 percent of the viable cells in the tumor were actually cancer cells, and in fact, three of those patients were pathologic complete responses in their primary tumor, which means that there was no evidence of the viable cancer in the tumor just 4 weeks after they were given one of two doses of nivolumab,” reported senior study author Drew Pardoll, MD, PhD, Director of Bloomberg~Kimmel Institute for Cancer Immunotherapy and Director of Cancer Immunology at Johns Hopkins School of Medicine.

“While it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation in a larger study, we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection,” he concluded.


IDO1 & PD-L1 Inhibitors

Results from the ongoing ECHO-203 clinical trial found that an immunotherapy treatment combining the IDO1 inhibitor epacadostat and the PD-L1 inhibitor durvalumab was safe in patients with advanced solid tumors, with safety data similar to treatment with durvalumab alone (Abstract CT177).

“Immune checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, have provided meaningful clinical benefits for patients with cancer; however, novel immunotherapy combination treatments are needed to improve efficacy with limited additive toxicity,” said Aung Naing, MD, FACP, Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. “This is the first report of IDO1 inhibition in combination with PD-L1 antagonism, and we found that epacadostat plus durvalumab was generally well-tolerated in patients with advanced cancers, with a safety profile consistent with previous reports of durvalumab monotherapy.

“ECHO-203 is part of the broader ECHO clinical development program investigating efficacy and safety of epacadostat as a core component of combination therapy in a broad range of solid tumor types as well as hematological malignancies,” he continued. “Ongoing clinical studies are evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors including pembrolizumab, nivolumab, and durvalumab.”

Researchers tested the combinatorial treatment in 34 patients with advanced pancreatic cancer, melanoma, NSCLC, or squamous cell carcinoma of the head and neck (SCCHN). Patients received doses of epacadostat ranging from 25 mg to 300 mg twice daily in combination with 3 mg/kg or 10 mg/kg of durvalumab every 2 weeks, according to investigators.

Common adverse events (AEs) included fatigue (32%), pruritus (severe itching; 15%), diarrhea, nausea, and rash (12% each); five patients discontinued treatment due to AEs. “As of Oct. 29, 2017, efficacy data for 15 patients with advanced pancreatic cancer treated at various dose levels revealed no responses,” researchers reported. Four patients had stable disease, resulting in a disease control rate of 27 percent; one patient discontinued treatment following clinical progression.

“Because pancreatic cancer has an immunosuppressive tumor microenvironment that generally excludes T cells, combinatorial therapies that enhance the immune response will be needed for an effective immunotherapeutic regimen,” explained Naing.

“However, as pancreatic cancer is not generally responsive to immunotherapy, these results were not a complete surprise,” he continued. “We found that epacadostat drug levels were slightly lower in pancreatic cancer patients who had prior pancreatic and duodenal surgeries, which are commonly performed in this patient population.”

Researchers are currently evaluating phase II expansions, with epacadostat doses of 100 mg and 300 mg in combination with 10 mg/kg of durvalumab, in patients with NSCLC, SCCHN, and urothelial carcinoma. “Since these tumor types have demonstrated efficacy with checkpoint inhibition monotherapy, they were considered more likely to potentially benefit from combination immunotherapy,” concluded Naing.


Pancreatic Cancer

New data suggests that calcium channel blockers (CCBs), specifically the short-acting form of CCBs, which are prescribed to treat high blood pressure, were associated with an increased risk of pancreatic cancer in postmenopausal women (Abstract 4946).

“Pancreatic cancer typically occurs in elderly individuals who also have chronic comorbid medical conditions, such as hypertension,” noted Zhensheng Wang, PhD, a postdoctoral associate at the NCI-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston. “Antihypertensive medication use has increased significantly; therefore, it is of great public health significance to address the potential association between antihypertensive medication use and risk of pancreatic cancer in the general population.”

A prospective cohort study was conducted that included 145,551 postmenopausal women ages 50-79 who were enrolled in the Women’s Health Initiative, a long-term national health study, between 1993 and 1998. Data was collected on any medications they were taking, including product and generic name, duration of use, and dosage form. Four types of antihypertensive drugs were analyzed: beta blockers, diuretics, angiotensin converting enzyme inhibitors (ACEi), and CCBs.

Researchers found that there was a 66 percent higher risk of incident pancreatic cancer among women who had ever used short-acting CCBs. Women who had used short-acting CCBs for 3 or more years were found to have a 107 percent higher risk of pancreatic cancer than those who had used other non-CCB antihypertensive drugs, investigators reported.

“Our findings on short-acting CCB use and pancreatic cancer risk are novel and of potential broad medical and public health significance if confirmed. Short-acting CCBs are still prescribed to manage hypertension, which is one of the components of metabolic syndrome, and metabolic syndrome is a possible risk factor for pancreatic cancer,” Wang concluded.


Updates in Melanoma

The KEYNOTE-054/EORTC 1325-MG phase III clinical trial, showed that a 1-year course of 18 doses of the immunotherapy agent, pembrolizumab, significantly reduced the risk of recurrence for patients with stage III melanoma who were at high risk of recurrence after surgery (Abstract CT001, N Engl J Med 2018; doi:10.1056/NEJMoa1802357).

“Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes,” noted Alexander M. M. Eggermont, MD, PhD, Director General of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, in a statement. “A patient’s risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis. In the case of a single positive node, the diameter must be greater than 1 millimeter.

“We were pleased to see that adjuvant pembrolizumab, given as a flat dose of 200 milligrams every 3 weeks after surgery for up to a year, which is 18 doses, significantly reduced the risk of recurrence for patients with high-risk stage III melanoma that has been completely resected,” he continued. “We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients.”

To date, two other checkpoint-based immunotherapies have been approved by the FDA for completely resected stage III melanoma in the adjuvant setting: ipilimumab, an anti-CTLA4 monoclonal antibody in October 2015, and nivolumab, an anti-PD-1 antibody, in December 2017.

Researchers reported that after a median follow-up of 1.25 years, 135 of the 514 patients randomized to pembrolizumab and 216 of the 505 patients randomized to placebo had been diagnosed with recurrent disease or had died. “An important aspect of this trial is that patients randomized to placebo who have recurrence are offered access to pembrolizumab,” said Eggermont. “This crossover design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse.”

Additional research highlighted at AACR explored the impact of the combination of CMP-001, an intratumoral Toll-like receptor 9 (TLR9) agonist, and pembrolizumab in patients with metastatic melanoma resistant to PD-1 (Abstract CT144). Preliminary findings show that the combination was well-tolerated and had clinical activity among this patient population.

“Checkpoint inhibition is quickly becoming a key tool for oncologists to treat cancer,” said Mohammed Milhem, MBBS, Clinical Professor of Internal Medicine at the University of Iowa, Iowa City. “However, there are many patients that either initially respond to checkpoint inhibition and then progress, or never respond to this therapy to begin with. Finding safe and effective therapies for these patients is critical.”

Researchers enrolled patients with advanced melanoma who had either not responded to or had progressed during prior anti-PD-1 therapy. As of March 27, 2018, 85 patients have been treated in the trial; 44 patients were enrolled in the dose-escalation phase, while 41 patients have been enrolled in the ongoing dose-expansion phase, investigators reported.

Throughout the completed dose-escalation phase, patients received CMP-001 via direct intratumoral injection at doses ranging from 1 mg to 10 mg in combination with pembrolizumab. There were two treatment schedules for CMP-001 administration: one injection per week for 7 weeks followed by every 3 weeks until discontinuation (weekly treatment); or one injection per week for 2 weeks followed by every 3 weeks until discontinuation (q3w treatment).

“To date, across both the dose-escalation and expansion cohorts, 15 patients have responded,” according to Milhem. The objective response rate (ORR) is 22 percent. The ORR is 23 percent and 15 percent for patients on weekly and q3w treatment, respectively.

“Based on these preliminary findings, the combination of CMP-001 and pembrolizumab appears to have a manageable safety profile and meaningful clinical activity,” Milhem noted, in a statement. “Additional larger studies in this patient population will need to be conducted to further evaluate the clinical benefit, but if the current results are confirmed, it appears that this combination could offer a new treatment option for patients with advanced melanoma who are not responsive to pembrolizumab.”

Catlin Nalley is associate editor.