Evidence-Based Oncology
July 2019
Volume 25
Issue 8

Research Report: ASCO 2019

Selected abstracts from the 2019 Annual Meeting of the American Society of Clinical Oncology.

Nivolumab, Ipilimumab Combo Demonstrates Clinical Benefit Among Adults With Pediatric Solid Tumors

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated significant clinical benefit in patients with solid pediatric tumors that progressed into adulthood—a patient population with few treatment options—according to new study findings.

According to the findings of the first cohort from the phase 2, single-arm study, during a median follow-up of 4.3 months, the combination yielded a 39.3% clinical benefit rate among the 30 patients evaluated.

“Solid pediatric tumors that appear in adulthood are a heterogeneous group characterized by a low incidence, lack of therapeutic options, and reduced survival,” wrote the investigators. While on the treatment, patients achieved a median overall survival of 6.8 months. All patients had locally advanced or metastatic pediatric malignancies that had progressed or were not candidates for traditional therapy.

“One case of metastatic esthesioneuroblastoma achieved a dramatic tumor response and represents the first patient with this extremely rare histology treated with immunotherapy,” noted the investigators. In addition to the 1 patient who achieved a deep partial response during treatment, 10 had stable disease, 17 had progressive disease, and 2 patients died before radiologic evaluation.

The patients, aged 20 to 75 years who were enrolled across 15 centers of the Spanish Group for Rare Cancer, included 4 with medulloblastoma, 4 with neuroblastoma, and 3 with Ewing family tumors. The majority (90%) of patients had received prior systemic therapy, with partial response representing the best response, which occurred in 37% of these patients. The median amount of previous treatment lines was 3.

The treatment regimen consisted of nivolumab 3 mg/kg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks for 6 months or until disease progression or discontinuation due to treatment toxicity, for a maximum of 24 months. Among the 30-person cohort, 6 patients have been treated for at least 6 months, with 1 discontinuing due to adverse events (AEs).

A total of 12 (40%) patients experienced adverse events of any grade and 6 (20%) experienced an AE possibly related to the treatment.


Mielgo X, Diaz-Beveridge R, Sepulveda JM, et al. Interim analysis of a phase II study of nivolumab combined with ipilimumab in patients with pediatric solid tumors in adulthood (GETHI021). Presented at: American Society of Clinical Oncology 2019 Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract: 2613.

Nivolumab, Ipilimumab Combo Yields Clinically Meaningful Responses in Advanced Hepatocellular Carcinoma

Nivolumab (Opdivo) monotherapy is currently indicated for the treatment of patients with hepatocellular carcinoma who were previously treated with the targeted therapy sorafenib (sold as Nexavar) based on the CheckMate 040 trial.

Assessing the safety and efficacy of nivolumab in combination with ipilimumab (Yervoy) among these patients, investigators have observed clinically meaningful responses and an acceptable safety profile.

These findings showed an overall response rate (ORR) associated with the combination that was double that seen with nivolumab therapy alone. During the CheckMate 040 trial, nivolumab monotherapy yielded an ORR of 14%. These new data on the treatment combination showed an ORR of 31%. Seven patients achieved a complete response with a median duration of response of 17 months. There was a disease control rate of 49%.

According to the investigators, this is the first report of efficacy and safety for this combination in the patient population.

With a cutoff date of September 25, 2018, the investigators observed a total of 148 patients (treated with sorafenib) randomized to 3 treatment groups:

• Group A: Four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks

• Group B: Four doses of nivolumab 3 mg/kg plus ipilimumab

1 mg/kg once every 3 weeks, each followed by nivolumab 240 mg once every 2 weeks

• Group C: nivolumab 3 mg/kg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks.

Patients were treated until disease progression or intolerable toxicity. At the end of 24 months of follow-up, there was an overall survival (OS) rate of 40%.

Patients in Group A demonstrated the greatest response, with a median OS of 23 months. At 12 months, OS was 61%, and at 24 months, OS was 48%.

Sixteen (32%) of the 50 patients achieved any response, with 4 experiencing a complete response and 12 experiencing a partial response. Nine patients experienced disease stability and 20 experienced disease progression.

In Group B, there was a median OS of 12 months among the 49 patients. At 12 months, OS was 56%, and at 24 months, OS was 30%. Fifteen patients achieved any response, with 3 experiencing a complete response and 12 experiencing a partial response. Five patients had disease stability and 24 experienced disease progression.

Median OS among the 49 patients in Group C was 13 months, with a 12-month survival rate of 51% and a 24-month survival rate of 42%. No patients achieved a complete response and 15 patients achieved a partial response; 9 experienced disease stability and 21 experienced disease progression.

Overall, the treatment combination was well tolerated, with 37% of all patients experiencing a grade 3 or 4 treatment-related adverse event. The most common adverse event was pruritus and rash, and 5% of patients had a treatment-related adverse event that led to treatment discontinuation.


Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. Presented at: American Society of Clinical Oncology 2019 Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract: 4012.

Entrectinib Demonstrates Efficacy in Rare Lung Cancer, Pediatric Solid Tumors

A pair of study abstracts presented at the annual meeting supported the efficacy of entrectinib among 2 different groups of patients, including patients with a rare form of lung cancer and pediatric and adolescent patients with solid tumors.

The first abstract1 reviewed data coming from 3 phase 1/2 single-arm clinical trials assessing the tyrosine kinase inhibitor entrectinib among 53 patients with ROS1-mutated non—small cell lung cancer (NSCLC). Due to the rarity of the tumor type and, therefore, low feasibility of a randomized trial, the investigators identified 69 patients from the Flatiron Health electronic health record–derived database who were treated with crizotinib between January 1, 2011, and June 30, 2018, to compare the efficacy of the 2 drugs. Crizotinib is currently considered standard of care for the patient population.

“In situations where you’re dealing with vary rare molecularly defined subpopulations of cancer patients, it’s often difficult to conduct a randomized study because of the low feasibility of being able to identify and recruit enough patients,” explained Neal J. Meropol, MD, vice president of Research Oncology at Flatiron Health, and an author of the abstract, in an interview with The American Journal of Managed Care ®. “Given the availability of high-quality, real-world data, there is now the potential to gain insights into the treatment outcomes of patients who are cared for in routine clinical practice, as well as gain a potential comparator to the results of single-arm clinical trials.”

Comparing the 2 groups of patients, the researchers observed significantly longer time-to-treatment discontinuation associated with entrectinib compared with crizotinib (14.6 vs 8.8 months). Progression-free survival also favored entrectinib (weighted hazard ratio, 0.44; 95% CI, 0.27-0.74). With a median follow-up of 15.5 months, median overall survival associated with entrectinib was not reached; the weighted median overall survival with crizotinib was 18.5 months.

“These results using real-world data support the hypothesis that entrectinib has meaningful activity against lung tumors with ROS1 fusions and may be superior to current standard of care. Although provocative, further study is certainly warranted to confirm these results,” said Meropol.

The second abstract2 focused on the use of entrectinib in children aged 4.9 months to adults aged 20 years with recurrent/refractory solid or central nervous system (CNS) tumors. Between May 2016 and October 2018, 29 patients with tumors with mutations in NTRK1/2/3, ROS1, or ALK, and neuroblastoma (NBL) were enrolled in the study; 28 were evaluated for response.

Among the 6 patients with CNS tumors, 1 achieved a complete response, 3 achieved a partial response, 1 achieved an unconfirmed partial response, and 1 has yet to be evaluated.

There were 8 patients with extracranial solid tumors, of whom 6 had a fusion; 1 achieved a complete response and 5 achieved a partial response. Among the 15 patients with NBL, 1 achieved a complete response.

“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1, or ALK fusions (11 out of 11), as well as in an ALK-mutated NBL,” wrote the researchers. “No responses were seen in tumors lacking aberrations in

target kinases.”

Based on the results, the researchers concluded that continued evaluation of entrectinib as a targeted therapy for solid tumors with these fusions, especially in high-grade CNS neoplasms, is warranted.


1. Doebele RC, Perez L, Trinh H, et al. Time-to-treatment discontinuation (TTD) and real-world progression-free survival (rwPFS) as endpoints for comparative efficacy analysis between entrectinib trial and crizotinib real-world ROS1 fusion-positive (ROS1+) NSCLC patients. Presented at: American Society of Clinical Oncology 2019 Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract: 9070. https://abstracts.

2. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. Presented at: American Society of Clinical Oncology 2019 Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract: 10009.

Which Predictors Could Identify the Most Costly Patients in Oncology?

Comorbidities, toxicities, and certain treatments received, including immunotherapy and bone marrow transplant, were the strongest predictors of high costs among patients with cancer, according to an abstract.

“Quality-based payment programs in medicine are currently being introduced nationally, aimed to improve care and reduce costs,” investigators wrote.

“This study aimed to evaluate the top spenders [TS] after cancer diagnosis and predict [the] TS at 2 separate time points using predictive analytics.”

The investigators collected data about patient characteristics, treatments, adverse events, and outcomes for patients treated for cancer at Mayo Clinic from 2007 to 2017. They obtained standardized costs over a 2-year period after first treatment from Mayo Clinic’s Cost Data Warehouse. Medicare reimbursements were assigned to all services and adjusted to the 2017 gross domestic product implicit price deflator for inflation. In the study, TS were identified as patients with costs greater than those in the 93rd percentile, which was $113,158 or higher, due to a substantial rise at that level.

The investigators used descriptive statistics and univariate analysis for comparison. Their prediction model had a training set of 80% and a validation set of 20%, using multivariate selection to predict TS. It was repeated using information available at 2 time points: consultation and last follow-up.

They identified 5626 TS from the 80,385 patients included. The mean overall cost was $44,953. The prediction models had ROC area under the curve statistics of 0.82 at the first time point and 0.89 at the second time point in the training set and 0.82 and 0.88, respectively, in the validation set, which indicated good prediction of high costs.

The investigators found these factors to be the most predictive of TS:

• Blood transfusions within 90 days of treatment (odds ratio [OR], 5.3)

• Bone marrow transplant (OR, 4.0)

• Mild liver disease (OR, 3.5)

• Hemiplegia, with an (OR, 3.4)

• Weight loss above 10% within 90 days of treatment, with an (OR, 3.3)

• Upper gastrointestinal cancer (OR, 3.0)

• “Other” cancer type (OR, 2.8)

• Immunotherapy (OR, 2.7)

• Hospitalizations within 90 days (OR, 2.4)

The investigators also found the highest costs resulted from hospital services in the TS and non-TS groups. The mean costs of hospital services were $114,258 and $13,185, respectively.

“This is the first study to predict with high accuracy the top spenders in oncology,” they wrote. “Our findings suggest that quality payment programs should adjust for comorbidities and that reducing toxicity may be an effective method at reducing costs.”


Waddle MR, Stross WC, Malouff TD, et al. Identifying and predicting the most costly patients in oncology. Presented at: American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 6633.

What Affects Time to Diagnosis in Children, Adolescents, and Young Adults With Solid Tumors?

Timw to diagnosis among children, adolescents, and young adults (AYAs) varies by cancer type and may be affected by clinical and sociodemographic factors, according to an abstract.

Investigators used claims data for commercially insured enrollees in a large United States health plan from OptumLabs’ data. They identified pediatric patients 14 years and younger and AYAs aged 15 to 39 years with soft tissue sarcomas (STS), bone tumors (BTs), and germ cell tumors (GCTs) diagnosed between 2001 and 2017 who were continuously enrolled for 6 months prior to their diagnosis.

Time to diagnosis was calculated as the number of days between a patient’s first medical encounter associated with a potential cancer symptom and their diagnosis date. The researchers compared median times from first symptom to diagnosis using the Wilcoxon Rank Sum Test. They used multivariable logistic regression to identify sociodemographic and clinical factors associated with intervals longer than 3 months from appearance of symptoms to diagnosis.

Of 11,395 total patients, 86% presented to medical care with symptoms before their diagnosis. A total of 2228 patients had STS, 1565 patients had BTs, and 5904 had GCTs. The most common symptoms reported were pain and swelling.

The researchers found that GCTs had the shortest median time to diagnosis (49 days), followed by BTs (91 days) and STS (92 days). There was a significant difference in median days to diagnosis by age:

• For patients with BTs, the median times to diagnosis was 69 days for those 14 years or younger, 77 days for patients aged 15 to 21 years, and 105 days for patients aged 22 to 39 years.

• For patients with GCTs, the median times to diagnosis was 96, 34, and 49 days, respectively.

There was not a significant difference in median days to diagnosis by age for STS. The investigators also found that being from a household with a college degree or higher level of education, as well as seeing a specialist other than an oncologist when symptoms first appeared, was associated with a longer delay in diagnosis. Older age and being male were associated with a shorter delay in diagnosis.

“In a commercially insured population, time to diagnosis varies by cancer type and is impacted by clinical and sociodemographic factors,” the investigators wrote. “Shorter time to diagnosis may represent delays in presenting to medical care or more acute presentations of symptoms. Therefore patient-reported symptoms and barriers to care data should be collected to better define strategies to reduce delays in diagnosis.”


Alvarez EM, Winestone L, McPheeters J, et al. Factors impacting time to diagnosis in pediatric, adolescent and young adult (AYA) patients with solid tumors. Presented at: American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract e21515.

Can Nivolumab Effectively Treat Metastatic RCC When Resources Are Limited?

Nivolumab (Opdivo) immunotherapy could effectively treat metastatic renal cell carcinoma (mRCC) in resource-constrained settings when the intervals between dosages are longer and when treatment is cut short for patients who respond, according to an abstract presented at the annual meeting.

“Nivolumab is now a standard second-line treatment for patients [with] mRCC who progress on first-line sunitinib or pazopanib,” the investigators wrote.

“Most Western centers use nivolumab for either 2 years duration, or indefinitely, or [until] severe side effects. Due to high drug cost and lack of insurance, it is difficult for most of our Indian patients to afford this duration of treatment. So, we decided to study the impact of increasing intervals between standard doses of nivolumab and stopping treatment early in responding patients [with] mRCC.”

The investigators onducted a single-center, retrospective study of patients with mRCC. Twenty-eight patients were treated with nivolumab between May 2016 and December 2018. Twenty-four patients initially received oral tyrosine kinase inhibitors (TKIs):

• 13 received sunitinib

• 10 received pazopanib

• 1 received sorafenib

The 4 patients who were not initially given TKIs received nivolumab as firstline therapy: 2 as a single agent and 2 with oral TKIs. Participants received either 3 mg/kg or 240 mg of nivolumab every 2 weeks for 6 initial cycles. The time between cycles was extended to 3 weeks if patients had a complete response (CR), a partial response (PR), or stable disease (SD).

The doses were extended to 4 weekly intervals after 9 months. The study’s end points were objective response rate (ORR), overall survival (OS), and adverse events. Patient response was assessed by Response Evaluation Criteria in Solid Tumors. The investigators found:

• 3 (10.7%) patients achieved a CR

• 7 (25.0%) patients achieved a PR

• 7 (25.0%) patients had SD

• 11 (39.2%) patients had progressive disease

Treatment was halted after 18 doses for the 3 patients who achieved a CR. The duration of follow-up after treatment ended ranged from 8 to 18 months.

The 3 patients who achieved a CR remained in CR. Of the 3 patients with SD, 1 received 22 cycles and 2 received 19 cycles. The OS at 1 year was 60%.

The median OS was not reached. “An ORR of 36% and OS at 1 year of 60% is the best we have seen. Longlasting responses, even after discontinuing therapy, have been seen. This enables us to reduce the cost of treatment without possibly losing efficacy, and this could be an important step forward for treating more patients with nivolumab in our resource-constraint setting,” the researchers concluded.


Rauthan A, Patil P, Yashas N, et al. Immunotherapy with nivolumab in metastatic renal cell carcinoma in resource constraint settings: impact of increasing intervals between standard doses, and stopping treatment early in responding patients. Presented at: American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract e16078.

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