PEMBROLIZUMAB FOR SOME RARE SARCOMAS

Sarcomas are rare malignancies, and effective therapies, apart from surgery and radiotherapy, are largely limited to chemotherapy and a handful of targeted agents.

But a few rare sarcoma subtypes may respond to therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), as French investigators demonstrated in the phase 2 AcSé trial.

Results from the study were presented online during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

"We all know that there is limited single-agent activity of PD-1 antibodies or PD-L1 antibodies as well as CTLA-4 antibodies in unselected sarcoma populations. But we also know that sarcomas are more than 150 different histotypes or molecular subtypes of disease," commented led author Jean-Yves Blay, MD, PhD, from Université Claude Bernard in Lyon, France.

Combinations of checkpoint inhibitors and antiangiogenic agents have been associated with prolonged progression-free survival (PFS) in alveolar soft part sarcomas (ASPSs), and single-agent activity of immunotherapeutic agents has been reported in other rare subtypes, including chordoma and rhabdoid tumors, he said.

But given the rarity and heterogeneity of sarcomas, investigators are increasingly "moving from a one-size-fits-all approach to a basket approach, and this was the intent of this clinical trial," Blay said.

AcSé Study Details

AcSé was a multicenter, open-label study involving patients with metastatic or treatment-refractory rare disease types, including sarcomas.

Patients with histologically confirmed diagnoses of rare sarcomas with metastatic disease or unresectable locally advanced tumors for whom there were no alternative treatment options were eligible.

Although there was no set definition of "rare," for most sarcoma subtypes included in the study, the incidence was less than 1 per one million population.

The cohort included 81 patients: 24 with chordoma, 14 with alveolar ASPS, five with desmoplastic small round cell tumor (DSRCT), six with SMARCA4-malignant rhabdoid tumor (SMBT), and 32 with diseases of other histotypes, including epitheliod sarcoma, myxoid liposarcoma, chondrosarcoma, angiosarcoma, and other unspecified types.

The median age of the patients was 48 years. Patients had received a median of two prior lines of therapy.

Patients received pembrolizumab 200 mg intravenously every 21 days for up to 2 years or until disease progression or unacceptable toxicity or until the physician or the patient decided to withdraw.

Some Objective Responses Seen

The primary endpoint was the objective response rate by intention to treat at 84 days. Among all patients with sarcoma, there were no complete responses, but five patients (6%) had a partial response. An additional 34 patients had stable disease, for a disease control rate of 48%.

The best responses by histotype were seen in 2 of 6 patients with SMBT, 1 of 5 patients with epitheloid sarcoma, 2 of 24 with chordoma, 5 of 14 with ASPS, and 2 of 22 with other types.

There were no objective responses among patients with myxoid liposarcoma, DSRCT, chondosarcoma, or angiosarcoma.

At a median follow-up of 228 days, the median PFS was 7.9 months. Median overall survival was 19.7 months. In all, 33 patients died during follow-up, after a median of three cycles.

In all, 60% of patients who had had an initial response experienced disease progression or withdrew before 84 days. These patients were counted as nonresponders in the intention-to-treat analysis.

PFS was superior among patients with ASPS, chordoma, and DSCRT compared with patients with diseases of other histologies.

Overall survival was also superior among patients with ASPS and chordoma compared with patients with other sarcoma subtypes.

Toxicities were recorded in 28 patients. Grade 3 events occurred in four patients (one case each of cognitive disorder, bullous pemphigus, febrile aplasia, and erysipelas). There was one case of grade-4 lipasemia.

Blay noted that the four subtypes for which pembrolizumab prolonged PFS ― ASPS, chordoma, SMBT, and DSCRT ― are not consistently associated with either PD-L1 expression, high tumor mutational burden, cell infiltrates, or tertiary lymphoid structures that might make them susceptible to a PD-1/PD-L1 inhibitor.

"Therefore, additional translational research is foreseen to understand the determinants of response in these sarcoma histotypes," he said.

Anti-PD-1 Recommended for Some Subtypes

Invited discussant Javier Martin-Broto, MD, PhD, from the Instituto de Biomedicina de Sevilla, Sevilla, Spain, commented that compared with other studies of immunotherapy with pembrolizumab (SARC028) or nivolumab (Opdivo; Alliance A091401), "the longer median progression-free survival observed in the current study could be highly related to the subtypes included in the study."

In other studies with drug combinations, the respective median PFS for chordoma, ASPS, and epithelioid sarcoma was 14 months, 10.9 – 12.4 months, and 5.53 – 6 months, he noted.

"Anti PD-1 agents should be included in the therapeutic arsenal of some subtypes as an example alveolar soft part sarcoma or malignant rhabdoid tumors. Anti-PD-1 immunomodulation deserves further investigations in tumors with misfunctioning SWItch/Sucrose Non-Fermentable complex, such as epithelioid sarcoma, dedifferentiated chordoma, and others," he said.

Martin-Broto also recommended that clinical research be conducted into regimens for sarcomas that combine chemotherapy with immunomodulators.

The study was supported by Merck Sharp & Dohme. Blay disclosed honoraria, consulting/advising, and research funding from MSD and others. Martin-Broto disclosed consulting/advising, speakers bureau participation, and research funding from several companies, not including MSD.

European Society for Medical Oncology (ESMO) Annual Meeting 2020: Abstract 1691O, presented September 21, 2020.

FIRST LINE PAZO[ANIB FOR ELDERLY SARCOMA PATIENTS

Doxorubicin is a standard of care in patients with advanced inoperable soft-tissue sarcoma. In the EPAZ study, German researchers tested whether pazopanib showed comparable efficacy to doxorubicin in the first-line treatment of elderly patients with soft-tissue sarcoma. Grünwald et al reported in the Journal of Clinical Oncology that pazopanib demonstrated noninferior efficacy to doxorubicin in first-line treatment of elderly patients with soft-tissue sarcoma, with improvement in treatment-related myelotoxicity. Approximately 40% of patients with soft-tissue sarcoma are aged 65 or older. A retrospective analysis in elderly patients indicated that being age 80 or older, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, and a large number of metastatic sites were associated with poor median overall survival, and indicated that younger and fitter patients were more likely to receive systemic therapy in clinical practice. Furthermore, a low percentage of patients 65 or older are included in clinical trials. Treatment with doxorubicin, a drug predominantly used in systemic therapy for advanced or metastatic soft-tissue sarcoma, is associated with adverse events such as neutropenia and febrile neutropenia. Given the vulnerability of geriatric patients, chemotherapy endangers this patient population and, as a consequence, hospitalization is frequently required. Pazopanib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor. It is associated with limited hematologic toxicity and has a global health status comparable to that of placebo. It is the standard of care in advanced and metastatic soft-tissue sarcoma after failure of treatment with anthracyclines. EPAZ Trial Design The study team assumed that the lack of severe hematologic toxicity would make pazopanib a suitable candidate for first-line treatment of elderly patients with soft-tissue sarcoma, thus minimizing the risk of febrile neutropenia. They designed the EPAZ trial to test whether pazopanib was noninferior to doxorubicin in patients with soft-tissue sarcoma aged 60 or older, while offering a better risk-benefit ratio for neutropenia and febrile neutropenia. Treatment-naive patients with an ECOG performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib at 800 mg once per day or doxorubicin at 75 mg/m2 once every 3 weeks for six cycles after patients were randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival, if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary endpoints. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range = 60­–88 years). Results Progression free-survival on the pazopanib arm was noninferior (HR = 1.00, 95% CI = 0.65–1.53). The incidence of grade 4 neutropenia and febrile neutropenia favored treatment with pazopanib. The objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms. Geriatric assessment revealed two or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. The overall incidence of toxicity remained similar for both treatments, but there were differences between adverse event profiles that may help tailoring treatment to individual needs in this population. The authors underlined that currently, predominantly fit elderly patients are selected to participate in the clinical trials. Future studies should focus on frail patients determined by geriatric assessment to develop a therapeutic strategy for this vulnerable patient population. The study authors concluded, “Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of soft-tissue sarcoma in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.” Disclosure: For full disclosures of the study authors, visit ascopubs.org. The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

AVAPRITINIB FOR PDGFR D842V GIST MUTATION

As reported in The Lancet Oncology by Heinrich et al, the phase I NAVIGATOR trial showed that the PDGFRA and KIT kinase inhibitor avapritinib produced a response in patients with PDGFRA D842V–mutant gastrointestinal stromal tumors (GIST).  

The study supported the January 2020 approval of avapritinib at 300 mg/d for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations.

Study Details

The international study included 46 patients with unresectable GIST (including 20 with PDGFRA D842V–mutant disease) in a dose-escalation phase, with an additional 36 patients with PDGFRA D842V–mutant disease being added in a dose-expansion phase.

In the dose-escalation phase, in which patients received 30 mg to 600 mg of avapritinib daily, the maximum tolerated dose was determined to be 400 mg daily. This dose was initially used as the starting dose in the dose-expansion phase, but due to toxicity (primarily an excess of grade 3 cognitive events and a frequent need for dose reduction), the starting dose was subsequently reduced to 300 mg once daily.

Overall, starting doses were < 300 mg/d in 30 patients, 300 mg/d in 32, 400 mg/d in 17, and 600 mg/d in 3. Treatment was given in continuous 28-day cycles until disease progression or unacceptable toxicity.

Among all 82 patients, the median age was 62 years. A total of 87% had received one or more previous tyrosine kinase inhibitors, and 21% had received five or more.

Responses

As of data cutoff (November 2018), median follow-up was 15.9 months. At this time, 66% of patents remained on treatment. Among all 56 patients with a D842V mutation treated with any dose, objective response on central review using modified Response Evaluation Criteria in Solid Tumors version 1.1 was observed in 49 (88%), with complete response in 5 (9%); an additional 7 patients (13%) had stable disease. Median duration of response was not reached, with 70% of responders having ongoing response at 12 months.

Progression-free survival was 100% at 3 months, 94% at 6 months, and 81% at 12 months. Overall survival was estimated at 100% at 6 months, 91% at 12 months, and 81% at 24 months.

Among the 28 patients who received a starting dose of 300 mg, objective response was observed in 26 (93%), with complete response in 1 (4%); an additional 2 patients (7%) had stable disease. 

Adverse Events

In the dose-escalation phase, dose-limiting toxicities occurred in two patients receiving 600 mg of avapritinib per day, consisting of grade 2 hypertension, dermatitis acneiform, and memory impairment in one patient, and grade 2 hyperbilirubinemia in the other.

Most treatment-related adverse events were grade 1 or 2. Among 32 patients treated with a starting dose of 300 mg/d, the most commonly reported treatment-related grade 1 or 2 adverse events were nausea (69%), diarrhea (41%), decreased appetite (38%), and fatigue (38%). Among 17 patients receiving a starting dose of 400 mg/d, the most commonly reported treatment-related grade 1 or 2 adverse events were nausea (71%), vomiting (47%), fatigue (47%), and periorbital edema (47%).

Across all doses, treatment-related grade 3 or 4 adverse events occurred in 47 (57%) of all 82 patients receiving avapritinib, with the most common being anemia (17%). Grade 3 or 4 events occurred in 65% of patients with a starting dose of 300 mg/d, with the most common being anemia (22%; all grade 3), and in 53% of those with a starting dose of 400 mg, with the most common being diarrhea (18%; all grade 3). 

Among all 84 patients, treatment-related serious adverse events of any grade occurred in 26%, with the majority being grade 3; the most common of any grade were anemia (4%), pleural effusion (4%), diarrhea (2%), and vertigo (2%). Treatment was discontinued due to adverse events in 15 patients (18%); 10 adverse events were considered treatment-related. No treatment-related deaths were reported. 

Cognitive effects and intracranial bleeding were considered adverse events of special interest. Cognitive adverse events irrespective of causality attribution occurred in 33 patients (40%; grade 1 in 19) and included memory impairment (30%), cognitive disorder (10%), confusional state (9%), and encephalopathy (2%). Intracranial bleeding occurred in two patients (2%, grade 3 in both).

The investigators concluded, “Our data show that avapritinib is clinically active in patients with PDGFRA D842V–mutated GIST. Most adverse events associated with avapritinib were grade 1–2; these adverse events were generally proportional to dose and exposure. Although cognitive effects are a concern, these effects were manageable for most patients through dose modifications…Overall, we found that avapritinib had clinical activity and a manageable safety profile in patients with advanced, PDGFRA D842V–driven GIST.”

Michael C. Heinrich, MD, of the VA Portland Health Care System and Oregon Health & Science University Knight Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Blueprint Medicines. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

RIPRETINIB FOR RESISTANT GIST

Treatment with oral ripretinib significantly prolonged survival in patients with advanced gastrointestinal stromal tumors (GIST) who did not respond or were intolerant to three other tyrosine-kinase inhibitors in the INVICTUS study.

The phase-3 study led the U.S. Food and Drug Administration (FDA) to approve ripretinib in May as fourth-line treatment for advanced GIST. Deciphera Pharmaceuticals, which markets ripretinib as Qinlock, funded the research.

The multicenter, randomized, double-blind, placebo-controlled trial enrolled 129 patients with advanced GIST whose disease progressed on at least imatinib, sunitinib and regorafenib or who were in tolerant to any of these drugs despite dose modifications.

Eighty-five patients received ripretinib (150 mg) and 44 received placebo once a day in 28-day cycles until disease progression or intolerable toxicity.

Median progression-free survival, the primary endpoint, was longer in the ripretinib arm than in the placebo group (6.3 months vs. 1.0 month; hazard ratio 0.15; P<0.0001). At the data cutoff date of May 31, 2019, 51 (60%) patients receiving ripretinib and 37 (84%) patients receiving placebo had disease progression or had died.

Eight (9.4%) patients in the ripretinib arm had a confirmed objective response (all partial) versus none of the patients in the placebo arm, although the difference failed to reach statistical significance.

Median overall survival was 15.1 months with ripretinib versus 6.6 months with placebo. "To our knowledge, ripretinib is the first agent to show an improvement in progression-free survival of such magnitude and a median overall survival above 15 months in this patient population," write Dr. Jean-Yves Blay of Centre Leon Berard, in Lyon, France, and colleagues in The Lancet Oncology.

"Notably, 29 (66%) of 44 patients in the placebo group crossed over to ripretinib at time of progression, and thus the improvement in overall survival could potentially be underestimated," they say.

Ripretinib was "generally well tolerated and associated with acceptable safety profile," they report.

The most common adverse events (>=20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome and vomiting.

The authors of an accompanying comment point out that ripretinib in the fourth-line shows "similar or better safety compared with other TKIs with a similar mode of action, has similar oncological activities to sunitinib in the second-line, and appears to be better than regorafenib in the third-line in terms of progression-free survival and objective response rate."

They also note that most patients who responded had durable responses. "These results might suggest that ripretinib could have greater and longer-lasting responses compared with other TKIs and, consequently, might be more effective in earlier treatment lines, which should be further investigated," write Dr. Toshirou Nishida of the National Cancer Center Hospital, in Tokyo, and Dr. Toshihiko Doi of the National Cancer Center Hospital East, in Chiba.

Finally, they say it will be critical to explore biomarkers to pinpoint which patients might benefit from ripretinib. "Active monitoring of biomarkers (e.g., by liquid biopsy) could help to identify the right medicine for the right patient at the right time and might improve the prognosis of patients with gastrointestinal stromal tumors."

Several of the INVICTUS study authors disclosed financial relationships with Deciphera Pharmaceuticals.

FDA APPROVED RIPRETINIB FOR GIST

On May 15, the U.S. Food and Drug Administration (FDA) approved ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.

INVICTUS Trial

Efficacy was evaluated in INVICTUS, an international, multicenter, randomized, double-blind, placebo-controlled trial in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. Patients were randomly assigned 2:1 to receive ripretinib at 150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Crossover was permitted at disease progression for patients assigned to receive placebo.

The major efficacy outcome measure was progression-free survival based on assessment by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors, version 1.1, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a preexisting tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included overall response rate by blinded independent central review and overall survival.

The trial demonstrated a statistically significant improvement in progression-free survival for patients in the ripretinib arm compared with those in the placebo arm (hazard ratio [HR] = 0.15, 95% confidence interval [CI] = 0.09–0.25, P < .0001). The median progression-free survival was 6.3 months (95% CI = 4.6–6.9) for ripretinib compared with 1.0 month (95% CI = 0.9–1.7) for placebo.

The overall response rate was 9% (95% CI = 4.2%–18%) in the ripretinib arm compared with 0% (95% CI = 0%–8%) in the placebo arm, though this difference was not statistically significant. The median overall survival in the ripretinib arm was 15.1 months (95% CI = 12.3–15.1) compared with 6.6 months (95% CI = 4.1–11.6) in the placebo arm, with a hazard ratio of 0.36 (95% CI = 0.21–0.62), though overall survival was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints.

The most common adverse reactions (≥ 20%) reported with ripretinib treatment were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.

The recommended ripretinib dose is 150 mg orally once daily with or without food.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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ASCO 2020-VDC/IE BETTER THAN VIDE IN EWING SARCOMA

A randomized trial found that for patients with newly diagnosed Ewing’s sarcoma, a chemotherapy regimen consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC/IE) offers better event-free survival (EFS) and overall survival (OS) than a regimen of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE; Abstract 11500).

The Euro EWING 2012 trial was conceived 10 years ago, when no novel agents were available to treat this malignancy, according to Bernadette Brennan, BSc, MBChB, MD, of Royal Manchester Children’s Hospital, in the United Kingdom, who presented the study during the ASCO20 Virtual Scientific Program. Dr. Brennan said that different chemotherapy regimens were used in Europe and in the United States, and it was considered worthwhile to compare the regimens directly in a randomized trial.

The study included 640 patients from 112 sites in 10 countries, randomly assigned to receive either VIDE or VDC/IE (320 patients in each group). Just over 40% of patients in each group were younger than age 14, and 58% were male. All patients had newly diagnosed Ewing’s sarcoma, including Ewing’s-like sarcoma without EWS translocation; 74% in each group had localized disease. The last patient was recruited in 2019, at which point an independent data monitoring committee advised the trial be discontinued because one regimen was demonstrating superior efficacy.

Dr. Patrick Leavey

EFS favored the VDC/IE regimen (Figure). There were 175 total events, including 102 in the VIDE group (32%) and 73 in the VDC/IE group (23%). Progression and recurrence were the most common events; 4% of the events in the VIDE group and 3% of those in the VDC/IE group were second primary tumors, and 9% and 3%, respectively, were death without recurrence. The 3-year EFS rates were 58% with VIDE and 69% with VDC/IE. The hazard ratio (HR) for EFS favoring VDC/IE was 0.66 (95% CI [0.49, 0.90]); an analysis showed that the posterior probability of the true HR being below 1 was 100%, and the probability of it being below 0.8 was 89%. This met the prespecified threshold whereby one of the regimens would be preferred if there was an 80% chance that it offered better EFS.

Figure. Event-Free Survival (Left) Overall Survival (Right)

Abbreviations: VDC/IE, vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide; VIDE, vincristine, ifosfamide, doxorubicin, and etoposide. View larger

A total of 105 patients in the study died, including 62 patients in the VIDE group (19%) and 43 in the VDC/IE group (13%). Most of the deaths were Ewing’s sarcoma–related; there were six deaths in the VIDE group related to the trial treatment, and no such deaths occurred in the VDC/IE group. The 3-year OS rates were 74% with VIDE and 82% with VDC/IE. The HR favoring VDC/IE was 0.64 (95% CI [0.43, 0.94]), and the posterior probability that the true HR was below 1 was 99%; for an HR of less than 0.8, the probability was 87%, again meeting the prespecified threshold.

The analysis considered only adverse events (AEs) of grade 3 to 5; 91% of patients in the VIDE group and 90% of those in the VDC/IE group had any such event during induction therapy. Some specific AEs did occur more frequently with VIDE, including hematologic AEs (85% vs. 77%) and febrile neutropenia (73% vs. 57%).

“The EURO EWING trial has demonstrated, with a high level of certainty, that EFS and OS are better in 2012 using VDC/IE,” Dr. Brennan said. “There is no excessive toxicity with VDC/IE, and it’s about 3 months shorter in treatment length, and there is some suggestion now that it is actually less toxic.” The results favoring VDC/IE were also confirmed in a subgroup analysis, she added, in which the regimen was better regardless of age, gender, disease type, tumor volume, or country.

“The EURO EWING trial has demonstrated, with a high level of certainty, that EFS and OS are better in 2012 using VDC/IE,” Dr. Brennan said.

Patrick Leavey, MD, of The University of Texas Southwestern Medical Center, was the discussant for the study. He noted that this study gave 14 cycles of chemotherapy, while others have opted for 17 cycles, and the optimal number remains in question. “Another chemotherapy question is yet to be answered,” he said. “And that is whether maintenance will be of value for a patient group in the localized setting.”

— Dave Levitan

ASCO 2020-3 YEARS OF IMATINIB FOR HIGH RISK GIST

Approximately half of deaths can be avoided with the use of 3 years of adjuvant imatinib in the first decade after surgery for high-risk gastrointestinal stromal tumors (GIST), according to long-term data from the Scandinavian Sarcoma Group XVIII/German trial (Abstract 11503).

“Three years of adjuvant imatinib is highly superior in efficacy with respect to recurrence-free survival (RFS) and, most importantly, overall survival (OS) as compared to 1 year of imatinib,” said Peter Reichardt, MD, of Helios Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Germany, who presented 10-year follow-up data as part of the ASCO20 Virtual Scientific Program.

“Three years of adjuvant imatinib is highly superior in efficacy with respect to recurrence-free survival and, most importantly, overall survival as compared to 1 year of imatinib.” - Dr. Peter Reichardt

The trial randomly assigned 400 patients with operable GIST and high risk for recurrence to receive 400 mg imatinib daily for either 12 months or 36 months after surgery. High risk for recurrence was defined according to modified National Institutes of Health Consensus Criteria as:

• Tumor size > 10 cm, or
• Tumor mitosis count > 10/50 high-power field of the microscope (HPFs), or
• Tumor size > 5 cm and mitosis count > 5/50 HPFs, or
• Tumor rupture spontaneously or at surgery.

The primary endpoint of the study was RFS. To date, the trial has found that 3 years of adjuvant imatinib improved OS compared with 1 year of imatinib at 54 and 90 months follow-up.

Dr. Giovanni Grignani

At 119 months follow-up, RFS and OS remained significantly better in patients assigned to 3 years of imatinib compared with 1 year of imatinib, Dr. Reichardt said. The 10-year RFS in the intention-to-treat population was 53% for 3 years of imatinib compared with 42% for 1 year of imatinib (HR 0.66, 95% CI [0.49, 0.87]; p = 0.003).

The 10-year OS in the intention-to-treat population was 79% for 3 years of imatinib compared with 65% in the 1-year group (HR 0.55, 95% CI [0.37, 0.83]; p = 0.004; Figure 1).

Figure 1. OS in the Intention-to-Treat PopulationView larger

The researchers also conducted several subgroup analyses.

“Most importantly, favoring the 3-year group were patients with local mitotic count more than 10, central mitotic count of more than 10, and KIT exon 11 mutation,” Dr. Reichardt said.

Outcomes were also analyzed in an efficacy population of patients who signed informed consent, had GIST at independent pathology review, and had no overt metastases at study entry. Among this group, patients assigned to 3 years of imatinib had significantly improved 10-year RFS (HR 0.70, 95% CI [0.52, 0.94]; p = 0.02) and OS (HR 0.50, 95% [0.32, 0.80]; p = 0.003) compared with 1 year of imatinib (Figure 2).

Figure 2. RFS and OS in the Efficacy Population**Patients who signed informed consent, had GIST at pathology review, and had no overt metastases at study entry.

Abbreviations: OS, overall survival; RFS, recurrance-free survival; GIST, gastrointestinal stromal tumors. View larger

There were some secondary cancers in both arms of the study, with prostate cancer being the most frequent. Cardiac events occurred in approximately 6% of patients.

In his discussion of the data, Giovanni Grignani, MD, of Candiolo Cancer Institute, Italy, said that the key point of this trial was the selection of a group of patients at high enough risk that imatinib activity could induce a reduction of 50% in the risk of death at 10 years.

“These outstanding results raise two questions,” Dr. Grignani said.

First, why was the OS curve more attractive than RFS? The OS plot is more attractive because the tails of the two curves are almost touching in the RFS curve.

“Previous studies may help to explain plot of recurrence-free survival,” he said. “Indeed imatinib cannot eradicate resistant clones left behind by surgeons, and imatinib induces a quiescent state that will end as we stop the drug with replication that will resume.”

In contrast, the tails of the OS curve opened up.

“This could be explained by positive interaction of imatinib with innate immunity, and inhibition of IDO leading to T-cell activation,” Dr. Grignani said.

The last question left open by this trial is whether oncologists treat only certain high-risk patients or whether oncologists can include other patients who have similar risk.

“My personal opinion is, ‘yes,’” he said, patients who have similar risk can be included as well.

— Leah Lawrence

STANDARD CHEMOTHERAPY BEST FOR SARCOMA

As reported in the Journal of Clinical Oncology by Alessandro Gronchi, MD, and colleagues, final results of a phase III trial conducted by the Italian, French, and Polish Sarcoma Groups showed no disease-free or overall survival benefit with use of histology-tailored vs standard anthracycline/ifosfamide neoadjuvant chemotherapy in patients with high-risk soft-tissue sarcoma.

Study Details

In the open-label trial, 287 patients from sites in Italy, Spain, France, and Poland with localized high-risk disease (grade 3, ≥ 5 cm) of an extremity or trunk wall belonging to one of five histologic subtypes were randomly assigned between May 2011 and May 2016 to receive standard anthracycline/ifosfamide neoadjuvant therapy (n = 145) or histology-tailored regimens (n = 142).

The histologic subtypes consisted of high-grade myxoid liposarcoma (n = 65), leiomyosarcoma (n =28), synovial sarcoma (n = 70), malignant peripheral nerve sheath tumor (n = 27), and undifferentiated pleomorphic sarcoma (n = 97). The histology-tailored regimens consisted of trabectedin for high-grade myxoid liposarcoma, gemcitabine/dacarbazine for leiomyosarcoma, high-dose prolonged-infusion ifosfamide for synovial sarcoma, etoposide/ifosfamide for malignant peripheral nerve sheath tumor, and gemcitabine/docetaxel for undifferentiated pleomorphic sarcoma.

Primary and secondary endpoints were disease-free survival and overall survival in the intent-to-treat populations.

Key Findings

The study was terminated early for futility, after the third prespecified futility analysis at a median follow-up of 1 year and after enrollment of 287 patients of the target population of 350.   

In total, 281 patients (97.9%) underwent planned surgery.

At final analysis, with median follow-up of 52 months, the projected 5-year probabilities for disease-free survival were 47% (95% confidence interval [CI] = 0.38–0.57) in the histology-tailored group vs 55% (95% CI = 0.46–0.63) in the anthracycline/ifosfamide group (hazard ratio [HR] = 1.23, P = .32). The projected 5-year probabilities for overall survival were 0.66 (95% CI = 0.57–0.75) in the histology-tailored group vs 0.76 (95% CI = 0.67–0.84) in the anthracycline/ifosfamide group (HR = 1.77, P = .02).

“In a population of patients with localized high-risk soft-tissue sarcoma, histology-tailored neoadjuvant chemotherapy was not associated with…better disease-free survival or overall survival, suggesting that anthracycline/ifosfamide should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk soft-tissue sarcoma.” 
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Among 230 patients evaluable for response on RECIST version 1.1 criteria, 13.6% of patients in the anthracycline/ifosfamide group and 6.2% of patients in the histology-tailored group had partial responses (no complete responses were observed), with 79.5% and 80.5% having stable disease.

No treatment-related deaths were observed.

The investigators concluded, “In a population of patients with localized high-risk soft-tissue sarcoma, histology-tailored neoadjuvant chemotherapy was not associated with…better disease-free survival or overall survival, suggesting that anthracycline/ifosfamide should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk soft-tissue sarcoma.”

Dr. Gronchi, of the Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, is the corresponding author for the Journal of Clinical Oncologyarticle. 

Disclosure: The study was funded by a grant from the European Union, PharmaMar, and others. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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POMALIDOMIDE APPROVED FOR SARCOMA KAPOSI BY FDA

On May 14, 2020, the U.S. Food and Drug Administration (FDA) expanded the indication of pomalidomide (Pomalyst) to include treating adult patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma after failure of highly active antiretroviral therapy and those with Kaposi sarcoma who are human immunodeficiency virus (HIV)-negative.

Study 12-C-0047

Efficacy was investigated in Study 12-C-0047, an open-label, single-arm clinical trial conducted by the National Cancer Institute. Twenty-eight patients (18 HIV-positive, 10 HIV-negative) received 5 mg of pomalidomide orally once daily on days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. All HIV-positive patients continued highly active antiretroviral therapy.

The main efficacy outcome measure was overall response rate, which included complete response, clinical complete response, and partial response. Response was assessed by the investigator according to the AIDS Clinical Trial Group Oncology Committee response criteria for Kaposi sarcoma.

Among the 18 HIV-positive patients, the overall response rate was 67% (95% CI = 41%–87%) with a median response duration of 12.5 months (95% CI = 6.5–24.9). Among the 10 HIV-negative patients, the overall response rate was 80% (95% CI = 44%–98%) with a median response duration of 10.5 months (95% CI = 3.9–24.2).

The most common adverse reactions including laboratory abnormalities (≥ 30% of patients) among those who received pomalidomide were decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea.

The recommended pomalidomide dose for Kaposi sarcoma is 5 mg once daily taken orally with or without food on days 1 through 21 of each 28‑day cycle until disease progression or unacceptable toxicity. Prescribing information indicates that highly active antiretroviral therapy as HIV treatment in should be continued for patients with AIDS-related Kaposi sarcoma.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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A NOVEL NEUROFIBROMATOSIS TREATMENT

The Food and Drug Administration has approved selumetinib for the treatment of pediatric patients aged 2 years and older with type 1 neurofibromatosis (NF1) with symptomatic, inoperable plexiform neurofibromas.

FDA approval was based on results from the phase 2 SPRINT Stratum 1 trial, in which 50 patients with NF1 received selumetinib as twice-daily oral monotherapy. Of this group, 33 (66%) patients had a partial response of at least a 20% reduction in tumor volume. There were no complete responses, according to a press release.

The most common adverse events were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, rash acneiform, stomatitis, headache, paronychia, and pruritus. Dose interruptions, dose reductions, and permanent drug discontinuation occurred in 80%, 24%, and 12% of patients, respectively.

Serious adverse reactions included cardiomyopathy, ocular toxicity, gastrointestinal toxicity, increased creatinine phosphokinase, and increased vitamin E levels and risk of bleeding, according to the press release.

"Previously, there were no medicines approved for this disease. This approval has the potential to change how symptomatic, inoperable NF1 plexiform neurofibromas are treated and provides new hope to these patients," Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer of Merck Research Laboratories, said in the press release.

SURGICAL MARGINS IN GIST ONLY RUPTURE MATTERS?

A post hoc observational study from the phase III EORTC 62024 trial of adjuvant imatinib in patients with localized gastrointestinal stromal tumors (GIST) showed that improvement in survival with R0 vs R1 resection was no longer evident when tumor rupture was excluded from the R1 category. The study was reported in JAMA Surgery by Alessandro Gronchi, MD, and colleagues.

“The difference in overall survival by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse overall survival.”
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Study Details

In the intergroup trial, performed between December 2004 and October 2008 at sites in 12 countries, 908 patients were randomly assigned after surgery to receive imatinib at 400 mg/d for 2 years (n = 454) or no adjuvant treatment (n = 454). Stratification factors included R0 and R1 resection, with tumor rupture included in the R1 category.

Patients had to have primary GIST with intermediate or high risk of relapse, no evidence of residual disease after surgery, and no prior malignancies or concurrent severe/uncontrolled medical conditions. The primary outcome measure for the current analysis was overall survival.

Key Findings

Median follow-up was 9.1 years. Overall, 743 patients (81.1%) underwent R0 resection (375 in the imatinib group and 368 in the observation group and 162 (17.8%) underwent R1 resection (77 and 85 patients). Of those with R1 resection, 97 (59.9%) had a tumor rupture.

Ten-year overall survival was 64.4% among patients with R1 resection vs 82.6% among patients with R0 resection. R1 resection was associated with poorer overall survival among all patients (hazard ratio [HR] = 2.05, 95% confidence interval [CI] =1.45–2.89) and in both the imatinib group (HR = 2.65, 95% CI = 1.37–3.75) and the observation group (HR = 1.86, 95% CI = 1.16–2.99).

When tumor rupture was excluded from the R1 category, there was no significant difference in overall survival for R1 vs R0 resection (HR = 1.05, 95% CI = 0.54–2.01).

R1 resection was also associated with significantly poorer relapse-free survival overall (HR = 1.98, 95% CI = 1.55–2.53) and in both the imatinib group (HR = 2.32, 95% CI = 1.64–3.30) and observation group (HR = 1.81, 95% CI = 1.29–2.54). With the exclusion of tumor rupture, the difference was no longer significant (HR = 1.35, 95% CI = 0.91–1.99).

The investigators concluded, “The difference in overall survival by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse overall survival.”

Dr. Gronchi, of the Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, is the corresponding author for the JAMA Surgeryarticle.

A NOVEL DRUG FOR EPITHELOID SARCOMAS? NOT SO STRONG DATA

On January 23, the U.S. Food and Drug Administration (FDA) granted accelerated approval to tazemetostat (Tazverik) for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of tazemetostat provides a treatment option that specifically targets this disease. When we brought tazemetostat’s application to the Oncologic Drugs Advisory Committee last month, the committee voted unanimously that the benefits of the drug outweighed the risks.”

Tazemetostat blocks activity of the EZH2 methyltransferase.

EZH-202

Efficacy was investigated in a single-arm cohort (cohort 5) of a multicenter trial (Study EZH-202) in patients with histologically confirmed, metastatic, or locally advanced epithelioid sarcoma. Patients were required to have INI1 loss (detected using local tests) and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received 800 mg of tazemetostat orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were confirmed overall response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (assessed by blinded independent central review), and duration of response.

The overall response rate for the 62 patients in cohort 5 was 15% (95% confidence interval = 7%–26%), with 1.6% having complete responses and 13% having partial responses; 67% of those responding had responses lasting 6 months or longer.

The most common adverse reactions (incidence ≥ 20% of patients) were pain, fatigue. nausea, decreased appetite, vomiting, and constipation.

The recommended tazemetostat dose is 800 mg taken orally twice daily with or without food.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

A NOVEL DRUG FOR RESISTANT GIST

On January 9, the U.S. Food and Drug Administration (FDA) approved avapritinib (Ayvakit) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbors platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. This approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation. Avapritinib is an investigational, oral precision therapy that selectively inhibits KIT- and PDGFRA-mutant kinases.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Clinical trials showed a high response rate with almost 85% of patients experiencing tumor shrinkage with this targeted drug.”

NAVIGATOR Trial

The FDA approved avapritinib based on the results of the phase I NAVIGATOR trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation. Patients received avapritinib at 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many patients experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).

For patients harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting 6 months or longer (31% of patients with an ongoing response were followed for less than 6 months).

Side Effects

Common side effects for patients taking avapritinib were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Avapritinib can cause intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued. Avapritinib can also cause central nervous system effects including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. If this happens, depending on the severity, avapritinib should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.

Health-care professionals should advise pregnant women that avapritinib may cause harm to a developing fetus or newborn baby. Additionally, the FDA advises health-care professionals to tell females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.

The FDA granted this application Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Avapritinib was also granted Fast Track designation and Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. 

The FDA granted approval of avapritinib to Blueprint Medicines Corporation.

SARCOMA RISK IN PATIENTS WITH HEREDITARY RETINOBLASTOMA

The risk of bone and soft-tissue sarcoma is markedly elevated in long-term survivors of hereditary retinoblastoma treated with radiation, researchers report.

"We provide novel data that after radiotherapy for hereditary retinoblastoma, if sarcoma develops, it occurs in distinctive patterns by the type of sarcoma and location on the body," Dr. Lindsay M. Morton of the National Cancer Institute, in Bethesda, Maryland, told Reuters Health by email. "These findings provide a potential roadmap for tailoring the screening approach for sarcomas among retinoblastoma survivors."

Radiotherapy is an established cause of sarcoma after hereditary retinoblastoma, but little is known about the long-term risk of sarcoma after hereditary retinoblastoma and whether the risks varied by specific tumor characteristics.

Dr. Morton and colleagues used data from 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed between 1914 and 2006 to quantify sarcoma risk and to analyze risk factors by anatomic location and histologic subtype.

Nearly half of the patients (44%) were also treated with chemotherapy. The median age at sarcoma diagnosis was 15.5 years for bone sarcomas and 33.5 years for soft-tissue sarcomas.

Compared with the general population, these survivors had a more than 2,000 times increased risk of bone sarcomas in the head and neck and a 169-fold increased risk of bone sarcomas in the body and extremities (with 21.7 and 12.0 cases per 10,000 person-years, respectively).

In contrast to patterns in the general population, the risk of bone sarcoma in these survivors decreased with increasing age, the researchers report in the Journal of Clinical Oncology, online October 17.

For head and neck bone sarcomas, the cumulative incidence rose sharply after age 5 years through adolescence and then increased more modestly through 60 years after retinoblastoma. For body and extremity bone sarcomas, the cumulative incidence also increased sharply after age 5 through adolescence but remained stable thereafter.

The risk of soft-tissue sarcoma in the head and neck was 542 times greater in hereditary retinoblastoma survivors than in the general public and was 45.7-fold greater for other regions of the body (with 25.0 and 11.9 cases per 10,000 person-years, respectively).

The risk of body and extremity soft-tissue sarcoma increased substantially with increasing age, but there was no association between attained age for head and neck soft-tissue sarcomas.

In cumulative-incidence analyses, the incidence of head and neck soft-tissue sarcoma rose steadily throughout the entire duration of follow-up, whereas soft-tissue sarcoma in other body regions rarely occurred before the fourth decade of life, at which point the incidence increased steeply.

Patients diagnosed before age 12 months had the highest risks for head and neck soft-tissue sarcoma, whereas age at diagnosis was not associated with the risk of body and extremity soft-tissue sarcoma.

Females were 41% less likely than males to be diagnosed with head and neck soft-tissue sarcoma, but they were twice as likely as males to be diagnosed with body and extremity soft-tissue sarcoma.

Use of chemotherapy, family history of retinoblastoma, and year of retinoblastoma diagnosis did not appear to influence the risk of either bone or soft-tissue sarcoma.

"This report should inform study design in assessing the efficacy of sarcoma screening in this high-risk population," Dr. Morton said. "For example, our data suggest that screening for bone sarcomas in the head should persist for decades following retinoblastoma because of persistently elevated risks, whereas screening for bone sarcomas in the extremities may no longer be needed after adolescence."

"Because no evidence-based screening protocols have been developed for retinoblastoma survivors to date, international collaboration will be essential for advancing research to optimize the long-term health and clinical care for these patients," she said.