The 2019 ASCO Annual Meeting featured a wealth of presentations on important topics. In addition to our regular news coverage of the meeting, we present below some highlights of other studies that add to our knowledge base for treatment of various cancers.

Olaratumab in Soft-Tissue Sarcoma

Olaratumab failed to improve overall survival in patients with advanced soft-tissue sarcoma in a variety of subtypes including leiomyosarcoma, according to results of the phase III ANNOUNCE trial reported at the Plenary Session.¹ As a result, no new patients will be permitted to receive olaratumab outside of ongoing clinical trials, and the drug will be withdrawn from the market.

These findings represent yet another phase III trial that did not replicate promising phase II results. A previous phase Ib/II trial compared doxorubicin plus olaratumab vs doxorubicin alone in advanced soft-tissue sarcoma and showed that the combination improved progression-free and overall survival. Based on those results, the U.S. Food and Drug Administration (FDA) granted olaratumab conditional approval awaiting results of ANNOUNCE.

William Tap, MD

“Sarcoma represents a rare and heterogeneous group of cancers, with 50 to 80 subtypes. Many of these subtypes represent a unique disease with distinct biology. Doxorubicin, alone or I combination, remains a standard of care,” noted lead author William Tap, MD, Chief, Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center, New York. “No agents have shown superiority to doxorubicin. [Soft-tissue sarcoma] remains a great area of unmet medical need ripe for scientific discovery.”

The ANNOUNCE investigators randomly assigned 509 adult patients with unresectable advanced or metastatic soft-tissue sarcoma to treatment with olaratumab plus doxorubicin vs placebo plus doxorubicin alone for eight cycles. Then patients with disease control continued on olaratumab or placebo until disease progression or toxicity.

Numerous sarcoma subtypes were represented in the study population, with 26 unique diseases in the ‘other’ category alone. For all patients with soft-tissue sarcoma, the median overall survival was 20.4 months with the addition of olaratumab vs 19.7 months for controls. In the leiomyosarcoma population, median overall survival was almost identical: 21.6 months and 21.9 months, respectively.

Jaap Verweij, MD

“This is the highest median overall survival in the placebo arm ever reported in a sarcoma trial,” Dr. Tap noted. “We attribute overall improvements in sarcoma survival in part to better supportive care as well as a better understanding of and improved treatment paradigms for individual sarcoma subtypes.”

Discussant Jaap Verweij, MD, of Erasmus University Medical Center, Rotterdam, The Netherlands, said, “The outcome is disappointing, but the authors are to be congratulated for performing a study of this rare heterogeneous cancer at an unprecedented rate. This disease is a double challenge for clinical trials due to the rarity and variety of subtypes.”

Mutational Profile in Sarcoma

In keeping with the theme of sarcoma tumor heterogeneity, a separate study found that patients with heavily pretreated advanced sarcoma who were treated onto genomically matched clinical trials had better outcomes compared to patients treated on non–genomically matched trials.2 Median overall survival was 22.1 months for those who were treated with agents targeted to mutations identified by genetic profiling vs 15.5 months for patients treated without respect to genetic-profiling results.

Recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear.

— Shiraj Sen, MD

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“Drug development in sarcoma remains challenging, with few effective FDA-approved therapies. Fortunately, recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear,” said lead author Shiraj Sen, MD, of Sarah Cannon Research Institute’s drug development program at the HealthOne location in Denver.

To gain a better idea of the value of genomic profiling in sarcoma, the investigators obtained clinical trial data and next-generation sequencing information for 406 patients with sarcoma treated in phase I trials at The University of Texas MD Anderson Cancer Center, Houston, from 2006 to 2018. Among a diverse array of sarcoma subtypes enrolled in these trials, it was identified that 23% of patients had potentially actionable genomic alterations identified by next-generation sequencing and were enrolled in clinical trials of genomically matched drugs. The other 77% of patients enrolled onto nonmatched clinical trials served as the comparator group.

Although there was no difference in objective response rate between the two groups, in addition to improved overall survival, the matched treatment arm had a significantly higher clinical benefit rate: 41% vs 19%, respectively (P < .0001). The study suggests when a potentially actionable alteration is identified in an individual with sarcoma, enrollment onto a genomically matched trial should be considered. “These findings suggest that molecular profiling should be considered in metastatic, refractory sarcomas. A prospective, biomarker-driven, genomically matched basket trial for these alterations is warranted in advanced sarcomas,” he added.

Surveillance Imaging in Lymphoma

Surveillance imaging after first remission may not be necessary in patients with follicular lymphoma, according to the results of a prospective study that questioned the standard practice of regular computed tomography (CT) scans.³ Previously, a smaller study suggested that CT scans did not improve outcome. The present study was undertaken in a larger cohort of patients to validate the value of surveillance imaging.

The study enrolled 117 patients with newly diagnosed follicular lymphoma who responded to initial therapy and then relapsed; they were treated at the University of Iowa and the Mayo Clinic. Clinical records and surveillance imaging data were obtained from patient medical records at relapse. Detection of relapse was classified as identified by clinical suspicion (medical history, physical exam, and/or laboratory findings) or by surveillance imaging in asymptomatic patients.

Jimmy Mao, MD

The median age of patients was 59 years, 61% were men, and the median time to relapse was 26 months. At a median postrelapse follow-up of 69 months, 63 relapses (56%) were detected through clinical suspicion and 50 (44%) were detected by surveillance imaging. (Four relapses were undetermined.) There was no difference in survival between the two groups.

“There is no survival benefit in patients receiving routine surveillance imaging after achieving first remission in follicular lymphoma. The common practice of performing this should be questioned,” said lead author Jimmy Mao, MD, of the Mayo Clinic in Rochester, Minnesota. Further reasons for questioning this practice include the fact that the majority of relapses were detected in patients who already had clinical signs and symptoms of relapse, scans create patient anxiety, and scans increase the cost of care.

“Further investigation of prognostic markers is warranted to identify high-risk patients who may benefit from surveillance imaging,” Dr. Mao noted. He said that additional prospective studies with larger populations are needed to validate this finding and to change the current practice guideline.

Active Surveillance for Renal Cell Carcinoma?

It appears to be safe to employ active surveillance and delay initiation of active systemic treatment for select patients with metastatic renal cell carcinoma (RCC), according to a retrospective study based on a large database from the Canadian Kidney Cancer information system.⁴

Based on the largest analysis of active surveillance in metastatic RCC to date, our data suggest a subset of patients may be safely observed without immediate initiation of systemic therapy.

— Igal Kushnir MD

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“We found that about 47% of all patients with metastatic RCC in [this database] between January 2011 and December 2016 met the criteria for active surveillance. The active surveillance cohort had notably better survival than the immediately treated cohort,” said lead author Igal Kushnir MD, of Ottawa Hospital Cancer Center, Canada. The median time on active surveillance was 14.2 months, which suggests that systemic treatment can be delayed for about a year for a large number of patients without a negative impact on survival.

The study included 1,711 patients with metastatic RCC diagnosed between 2011 and 2016. Criteria for active surveillance included starting systemic therapy at least 6 months after diagnosis (370 patients, cohort A1) or never receiving systemic therapy and having overall survival for at least 1 year (493 patients, cohort A2). Patients who started systemic therapy < 6 months after diagnosis were cohort B (848 patients).

Estimated 5-year survival was 70.2% for cohort A vs 32.1% for cohort B. Patients in cohort A had fewer sites of metastatic disease compared with cohort B (P < .0001). The rate of metastasectomy was higher in cohort A: 23% vs 5%, respectively. After adjusting for age and International Metastatic RCC Database Consortium risk criteria, overall survival and time to treatment failure were longer in cohort A1 vs cohort B.

“Based on the largest analysis of active surveillance in metastatic RCC to date, our data suggest a subset of patients may be safely observed without immediate initiation of systemic therapy. It appears that metastasectomy can help delay the need for systemic therapy and potentially even contribute to improved survival,” Dr. Kushnir told listeners.

The study did not identify specific clinical markers for selecting patients for active surveillance. At present, that decision falls to the treating oncologist.

“It is probably safe to defer systemic treatment for patients with metastatic RCC who are not experiencing visceral crises or disease-related symptoms. At the next assessment, an experienced medical oncologist can determine whether active surveillance is appropriate based on growth kinetics of the tumor,” he said.

Low-Fat Diet May Reduce Breast Cancer Deaths

Data from the Women’s Health Initiative Dietary Modification (WHI DM) Trial after nearly 20 years follow-up, showed that the adoption of a low-fat dietary pattern (with increased vegetables, fruits, and grains) significantly reduced the risk of deaths from breast cancer (death directly attributed to the cancer) and death after breast cancer (breast cancer followed by death from any cause).5 In the study, 48,835 postmenopausal women aged 50 to 79 years, with no prior cancer, were randomly assigned, between 1993 to 1998, to a usual-diet comparison group or a dietary-intervention group. The dietary intervention, with group contacts with study nutritionists, continued through 8.5 years.

These findings provide the first randomized clinical trial evidence that any intervention can reduce a postmenopausal woman’s risk of dying from breast cancer.

— Rowan Chlebowski, MD, PhD

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During the intervention period, the low-fat group developed 8% fewer breast cancers and averaged 3% weight loss, but they did not experience a significant reduction in deaths from breast cancer. With long term follow-up, a statistically significant, 21% lower risk of death from breast cancer and a 15% lower risk of death from any cause after a breast cancer diagnosis, emerged, reported Rowan Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California.

“To our review, these findings provide the first randomized clinical trial evidence that any intervention can reduce a postmenopausal woman’s risk of dying from breast cancer,” Dr. -Chlebowski said. “The diet is one of moderation, and after nearly 20 years of follow-up, the health benefits are still accruing.”

Isatuximab Boosts Benefit of Pomalidomide/Dexamethasone

The regimen of isatuximab/pomalidomide and low-dose dexamethasone achieved a 40% reduction in disease progression or death compared to pomalidomide/dexamethasone alone in patients with relapsed or refractory multiple myeloma in the phase III ICARIA-MM trial.⁶ Median progression-free survival was 11.5 months with the isatuximab regimen compared with 6.5 months with pomalidomide/dexamethasone (hazard ratio [HR] = 0.596; P = .001).

Paul Richardson, MD

Although overall data are immature, a trend for a survival benefit also emerged, said Paul Richardson, MD, of Dana-Farber Cancer Institute, Boston. “This outcome is noteworthy because this trial included a particularly difficult-to-treat, relapsed and refractory patient population that was, in my view, highly reflective of real-world practice,” Dr. Richardson said.

The open-label, multicenter phase III ICARIA-MM trial included 307 patients with relapsed or refractory multiple myeloma who received at least two prior lines of treatment, including lenalidomide and a proteasome inhibitor. Isatuximab was administered intravenously at 10 mg/kg once weekly for 4 weeks, then biweekly, for 28-day cycles in combination with standard pomalidomide and dexamethasone for the duration of treatment.

The progression-free survival benefit held up across multiple patient subgroups, including those with high cytogenetic risk (HR = 0.66), and those refractory to lenalidomide (HR = 0.59), a proteasome inhibitor (HR = 0.58), and both lenalidomide and a proteasome inhibitor (HR = 0.58), he said.

With isatuximab as part of the regimen, response rates were significantly higher, the median time to response was sooner, the achievement of minimal residual disease negativity was more likely, and the median time to next therapy was not reached. Grade ≥ 3 treatment-emergent adverse events occurred in 86.8% of the isatuximab arm compared with 70.5% of the control arm.

Subcutaneous Daratumumab Effective and More Convenient

In the randomized phase III COLUMBA trial of 522 patients with relapsed or refractory myeloma, a subcutaneous flat-dose version of daratumumab proved to be noninferior to, and more convenient than, the standard intravenous formulation.⁷

Daratumumab subcutaneously has a reduced treatment burden, due to a considerably shorter administration duration.

— Maria-Victoria Mateos, MD, PhD

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The objective response rate was 41.1% with subcutaneous daratumumab at 1,800 mg and 37.1% with the intravenous 16‑mg/ kg formulation, meeting the criteria for noninferiority. Maximum concentrations evaluated on day 1 of cycle 2 also met the criteria for noninferiority of pharmacokinetics. Median progression-free survival was 6.1 months with intravenous daratumumab vs 5.6 months with the subcutaneous formulation (P = .9258), and the 6-month overall survival rate was 83.0% and 87.5%, respectively (P = .6032), reported Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.

Importantly, the median duration per infusion was 5 minutes with the subcutaneous formulation (at every visit), down from ≥ 3 hours in the intravenous group. The first intravenous infusion lasted a median of 7 hours, the second infusion lasted 4.3 hours, and subsequent infusions lasted 3.4 hours, she said.

The risk of infusion-related reactions was reduced by 72% with subcutaneous delivery (12.7% vs 34.5%; P < .0001), although most reactions in both arms were mild. Injection-site reactions occurred in 7% of the subcutaneous treatment arm, and all those reactions were also mild. Patients reported much greater satisfaction with the subcutaneous formulation.

“Daratumumab subcutaneously has a reduced treatment burden, due to a considerably shorter administration duration, and patients treated with daratumumab subcutaneously reported higher satisfaction with therapy,” Dr. Mateos said.

The manufacturer plans to submit an application to the FDA for the subcutaneous formulation, which consists of daratumumab plus the recombinant human hyaluronidase PH20.

T-DM1 Effectively Treats Salivary Gland Tumors

An effective treatment may have been identified for a rare tumor—salivary gland carcinoma—specifically, in the 8% of cases that are HER2-amplified. Currently, there is no approved treatment for metastatic salivary gland cancer, but at the ASCO Annual Meeting, researchers reported success with the antibody-drug conjugate trastuzumab emtansine (T-DM1).⁸

Bob T. Li, MD, MPH

In a multihistology basket trial, 10 heavily pretreated patients with HER2-amplified salivary gland cancers were treated with T-DM1 at 3.6 mg/kg every 3 weeks.Nine of the 10 responded (90%), including 5 patients (50%) who achieved complete responses after prior trastuzumab, pertuzumab, and antiandrogen therapy. After a median follow-up of 12 months, the median duration of response (range = 2–19+ months) and median progression-free survival (range = 4–22+ months) had not been reached, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York.

“Trastuzumab emtansine is highly efficacious in patients with HER2-amplified salivary gland cancers as identified by next-generation sequencing,” he said. “This study has met its primary endpoint, and cohort expansion is warranted to confirm these results.”

TPEx Regimen in First-Line Treatment of Head and Neck Cancer

As a first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma, a large randomized trial named TPExtreme confirmed the encouraging survival results achieved with the TPEx regimen, vs the EXTREME regimen, in a previous phase II study called GORTEC TPEx.⁹

Joël Guigay, MD

“The taxane-based TPEx regimen appears to be a new first-line treatment option, with a shorter time on chemotherapy and significantly lower toxicity than the EXTREME regimen,” said Joël Guigay, MD, of the Antoine Lacassagne Comprehensive Cancer Centre in Nice, France.

The EXTREME regimen (six cycles of fluorouracil, cisplatin, and cetuximab followed by cetuximab maintenance) is the current standard first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. The open-label study presented at the Annual Meeting compared it to the TPEx regimen (four cycles of docetaxel/cisplatin/cetuximab followed by cetuximab maintenance) in 539 patients.

Patients on the TPEx arm were more likely to complete all chemotherapy (72% vs 44%), to go onto maintenance (73% vs 53%), and to have fewer treatment delays (10% vs 27%), and these patients were less likely to switch from cisplatin to carboplatin (9% vs 34%). Toxicity during chemotherapy was lower with TPEx, with grade ≥ 4 events observed in 34% vs 50% with EXTREME (P < .001).

At the time of analysis, with a median follow-up of 30 months, overall survival was similar—14.5 months with TPEx vs 13.4 months with EXTREME—and the 2-year overall survival rates were 28.6% and 21.0%, respectively. ■

DISCLOSURE: Dr. Tap has served in a leadership position for Atropos Pharmaceuticals and Certis Oncology Solutions; owns stock in Atropos and Certis Oncology Solutions; has served in a consulting or advisory role for Agios, Blueprint Medicine, Daiichi Sankyo, Eisai, EMD Serono, GlaxoSmithKline, Immune Design, Janssen, Lilly, Loxo, Nanocell, and Novartis; has received research funding from BioAtla, Blueprint Medicines, Daiichi Sankyo, Deciphera, Immune Design, Lilly, Novartis, Plexxikon, and Tracon Pharma; and has patents for companion diagnostics for CDK4 inhibitors, methods of treating metastatic sarcoma using talimogene laherparepvec, and pembrolizumab combination therapy. Dr. Verweij has held a leadership position at Octimet; holds stock in Octimet; has received honoraria from Basilea, Genmab, InteRNA, Novartis, Octimet, Sanofi, and XBiotech; has served in a consulting or advisory role for Basilea, Genmab, InteRNA, Novartis, Sanofi, Sotio, and XBiotech; and has been reimbursed for travel, accommodations, and expenses from Basilea and Sanofi. Dr. Sen has served in a consulting or advisory role for Daiichi Sankyo and has received institutional research funding from BioAtla, Exelixis, Jacobio, and Loxo. Dr. Mao reported no financial disclosures. Dr. Kushnir owns stock in Teva and has received a research grant from Astellas Pharma. Dr. Chlebowski has served as a consultant or advisor for Amgen, AstraZeneca, Genentech, Immunomedics, Novartis, Pfizer, and Puma, and has served on speakers bureaus for AstraZeneca, Genentech, and Novartis. Dr. Richardson has served in a consulting or advisory role for Celgene, Janssen, and Takeda and has received research funding from Celgene and Takeda. Dr. Mateos has received honoraria from Amgen, Celgene, Janssen-Cilag, and Takeda and has served in a consulting or advisory role for AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, PharmaMar-Zeltia, and Takeda. Dr. Li has served in a consulting or advisory role for Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific and has received institutional research funding from Amgen, AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, Grail, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Guigay has served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, Innate Pharma, and Merck Serono and has received institutional research funding from Bristol-Myers Squibb and Merck Serono.

REFERENCES

1. Tap WD, Wagner AJ, Papai Z, et al: ANNOUNCE: A randomized, placebo-controlled, double-blind, phase III trial of doxorubicin + olaratumab vs doxorubicin + placebo inpatients with advanced soft tissue sarcoma. 2019 ASCO Annual Meeting. Abstract LBA3. Presented June 2, 2019.

2. Sen S, Pestana R, Hess KR, et al: Precision oncology in sarcoma drug development: Impact of genomic matching on response, clinical benefit, and survival in sarcoma patients on phase 1 trials. 2019 ASCO Annual Meeting. Abstract 11018. Presented June 1, 2019.

3. Mao J, Strouse CS, Goldman M, et al: Impact of surveillance imaging after first remission in follicular lymphoma. 2019 ASCO Annual Meeting. Abstract 7536. Presented June 3, 2019.

4. Kushnir I, Basappa NS, Ghosh S, et al: Active surveillance in metastatic renal cell carcinoma: Results from the Canadian Kidney Cancer information system. 2019 ASCO Annual Meeting. Abstract 4516. Presented June 3, 2019.

5. Chlebowski RT, Aragaki AK, Anderson GL, et al: Low-fat dietary pattern and long-term breast cancer incidence and mortality: The Women’s Health Initiative randomized clinical trial. 2019 ASCO Annual Meeting. Abstract 520. Presented June 2, 2019.

6. Richardson PG, Attal M, S. Rajkumar SV, et al: A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone vs pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8004. Presented June 2, 2019.

7. Mateos M-V, Nahi H, Legiec W, et al: Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous vs intravenous daratumumab administration in patients with relapsed or refractory multiple myeloma: COLUMBA. 2019 ASCO Annual Meeting. Abstract 8005. Presented June 2, 2019.

8. Li BT, Shen R, Offin M, et al: Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers: Results from a phase II basket trial. 2019 ASCO Annual Meeting. Abstract 6001. Presented May 31, 2019.

9. Guigay J, Fayette J, Mesia R, et al: TPExtreme randomized trial: TPEx vs Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma. 2019 ASCO Annual Meeting. Abstract 6002. Presented May 31, 2019.