by Arifi Samia, Hassan II University Hospital, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco

The European Society for Medical Oncology (ESMO) congress was held virtually from 19 to 21 September, 2020.

Sarcomas and gastrointestinal stromal tumours (GISTs) were subject of various oral presentations and posters.

A brief summary of selected researches is presented.

Gastrointestinal stromal tumours

NAVIGATOR: Long term efficacy and safety of avapritinib in D842V mutant- GISTs

GISTs are driven by various primary and secondary oncogenic mutations.

Platelet-derived growth factor receptor alpha (PDGFRA) mutations represent 5 to 6%.

Approximately, 75% of PDGFRA-mutated tumors results in an exon 18 D842V substitution.

This mutation is highly resistant to all currently approved kinase inhibitors (TKI).

Avapritinib is a novel tyrosine kinase inhibitor that potently inhibits PDGFRA D842V.

As reported in the lancet by Michael Heinrich and colleagues, the results of phase I NAVIGATOR (NCT02508532) trial have shown antitumour activity of Avapritinib in patients with advanced GISTs harboring PDGFRA exon 18 mutation including D842V, and a tolerable safety profile.

These results led to the US Food and Drug Administration approval of avapritinib in patients with exon 18 PDGFRA- mutant GISTs.

This year in ESMO annual meeting, updated results on long-term efficacy and safety in PDGFRA D842V-mutant GISTs were presented with data as of March 9; 2020 and a median follow-up of 26 months.

Of note, NAVIGATOR trial is a two-part, open label, multicenter, single arm, phase I study.

The dose escalation part (30-600 mg) included patients with unresectable GISTs; Kit mutant (n=23), PGFRA D842V (n=20), and PFGDRA non D842V (n=3).

The dose expansion part (300/400 mg) included patients with unresectable PDGFRA D842V mutant regardless of previous therapy (n=36), or GISTs with other mutations that only received imatinib (n=42) or that progressed on imatinib and one or more TKI (n=126).

The maximum tolerated dose was 400 mg and the recommended phase 2 dose was 300 mg.

The activity of avapritinib was assessed in patients with PDGFRA D842V mutation (N=56), and the safety was assessed in all patients (n=250). 

In the D842V population, the median age was 64 (25-90), 70% were men, and the majority of patients had metastatic disease and large tumours.

An overall response rate (ORR) of 91% (95% CI 80-97) was achieved in patients treated at any dose level.

Patients treated at 300/400 mg achieved an ORR of 95% (95% CI 82-99) with 5(13%) complete responses (CR), 31 (82%) partial responses (PR), and 2 (5%) stable disease.

Two of the 5 TKI naïve patients achieved a CR and 3 had a PR.

The median duration of response was 22 months (95% CI 14–NR).

Patients who received less than 300 mg (n=17), still achieved an ORR of 82% (95% CI 57-96), with 2 (12%) CR and 12 (71%) PR.

In patients receiving 300/400 mg, median PFS was 24 months (95% CI 18–NR), and median OS was not reached.

PFS and OS rates at 36 months were 34% and 71% respectively.

The safety profile in PDGFRA D842V mutant patients was similar to the overall study population.

Most common adverse events were nausea, anemia, diarrhea, fatigue, cognitive impairment, and peri-orbital edema.

Many of these events are reported with other TKI, nevertheless neurological toxicities require a careful evaluation in the future.

Treatment related events led to treatment discontinuation in 21% in PDGFRA D842V mutant cohort.

No drug-related deaths were reported. 

According to these results Avapritinib should be considered the new standard of care in first line setting for patients with unresectable/metastatic PDGFRA D842V- mutant GISTs.

Adverse events are manageable, however, a close monitoring for central nervous system toxicities with appropriate dose reduction is required.   

INVICTUS3: Post primary data analysis Data cutoff 9 March, 2020

Updated PFS, OS, and safety profile in the placebo-controlled phase III INVICTUS trial were presented during the mini-oral session4.

In this trial 129 patients who have progressed on 3 or more TKI including imatinib or are intolerant to multiple TKI were randomised (2:1) to Ripretinib, a novel TKI that targets multiple Kit and PDGFRA mutations, 150 mg once daily or placebo.

Upon disease progression, patients on placebo could cross over to Ripretinib.

After additional 9 months from the primary analysis (cutoff date March 9,2020), a similar median PFS of 6.3 months (95% CI 4.6−8.1) in the Ripretinib arm was reported versus 1.0 month (95% CI 0.9−1.7) for patients on placebo arm with an HR=0.16 (95% CI 0.1-0.27).

The median OS in the Ripretinib arm has extended from 15.1 months to “not reached” (95% CI 13.1–NE) versus 6.3 months (95% CI 4.1−10.0) in the placebo arm with an HR of 0.43 (95% CI 0.26-0.67).

The ORR was 11.8% (95% CI 5.8-20.6) in Ripretinib versus 0 in placebo arm.

The median duration of response was long 14.5 months (95% CI 3.7-not estimable).

The safety profile was favorable and consistent with the previous results.

The increase in treatment emergent adverse events (TEAE) and the number of new TEAEs leading to dose modification or death was minimal. 

Ripretinib 150 mg once daily is currently approved by the FDA for fourth line or further line therapy for advanced GISTs.

According to presented data, Ripretinib continues to provide clinically meaningful benefit with no additional safety concerns after additional 9 months follow-up.

A significant improvement in OS as compared with the group receiving placebo despite a crossover design suggests the importance of an early Ripretinib treatment in this patient population.

Ripretinib: New dosing strategy in treating patients with advanced GISTs

In the Phase I trial of Ripretinib; NCT025710365, 142 patients with advanced GIST were enrolled.

Participant had at least one prior targeted therapy (2nd line, n=31; 3rd line, n=28; and ≥4th line, n=83).

Patients were treated with Ripretinib 150 mg once daily (QD) and may dose escalate to Ripretinib 150 mg twice daily (BID) after disease progression.

A PFS benefit from increasing dosage of Ripretinib was observed in patients across all lines of therapy (table 1).

A substantial proportion of patients do achieve a prolonged PFS on 150 mg BID.

Safety was similar between the two dosing regimens; the most common TEAEs (≥10%) were alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia, muscle spasms, rash, weight decreased, abdominal pain, diarrhea, back pain, vomiting and decreased appetite.

Anemia and dyspnea were reported in ≥10% of patients receiving 150 mg BID.

Escalation to Ripretinib 150 mg BID should be investigated in the future as new therapeutic option in patients progressing under standard dose of Ripretinib.

Predictive markers are needed to better define the period and the group of patients benefiting from dose escalation.

There are several molecular mechanisms underlying secondary resistance in GISTs and their inhibition may require different drug levels.

However, the additional efficacy of dose escalation may not necessarily relate to overcoming resistance, but drug clearance mechanisms.

More researches are required to investigate the correlation between the plasma levels and outcome.

Based on this study results, a randomised trial comparing the two doses; 150 mg QD versus 150 mg BID could be interesting to explore whether a higher dose of Ripretinib may provide better clinical outcome in patients with advanced GISTs.

Table 1: median PFS across all treatment lines, PFS period 1 (PFS1; 150 mg QD) was calculated from Cycle 1, Day 1 to PD; PFS2 (150 mg BID) from date of IPDE to 2nd PD or death.

Soft tissue sarcoma

Pembrolizumab provided response in selected subtypes of rare sarcomas AcSé Pembrolizumab trial is a phase II non-randomised parallel arm, open-label, multicenter which investigated the efficacy and safety of pembrolizumab monotherapy in rare cancers.

Patients ≥15 years, ECOG ≤1 with advanced disease that was resistant to standard treatment or with no alternative treatment options were eligible.

From September 2017 to May 2020, 81 patients with rare sarcoma; chordoma (n=24), alveolar soft-part sarcoma (ASPS, n=14), desmoplastic small round cell tumour (DSRCT; n=6), smarca4-malignant rhabdoid tumour (SMBT; n=6) and others (n=31) were enrolled.

The median age of this cohort was 48 (33-65), 52% were men, and the median previous lines was 2 ranging from 1 to 3.

The primary endpoint was ORR according to RECIST v1.1 measured at least at day 84 /- 7 days. and secondary endpoints were clinical benefit rate, best response, DOR, PFS, OS and safety.

Pembrolizumab was administered at 200 mg every 21-day up to progressive disease or unacceptable toxicity or for a maximum of 2 years.

Patients received a median of 6 cycles (IQR, 4-11, from 1 to).

ORR was 6% according to the study definition and 15 % if any time (best response).

Response rate varied by histotype; 2/6 (33.3%) responses were observed in SMBT, 5/14 (35.7%%) in ASPS, 0/6 in DSCRCT, 2/24 (8%) in chordoma, and 2/22 (9%) showed response in other histotypes (p = 0.010).

Survival rates also varied by histotype (p=0.013) with a better PFS chordoma, ASPS, and DSCRCT as compared to other histotypes.

Median OS was significantly better in chordoma, and ASPS cohort as compared to other histotypes.

Regarding the safety endpoint, trial discontinuation after receiving a median of 4 cycles was reported for 62 (67.5%) patients. 13 TRAEs were recorded; 6 grade 1-2, 6 grade 3 in 4 patients, and 1 grade 4.

Of the 7 grade 3 or 4 TRAEs, 4 results in treatment withdrawals and 2 treatment interruption.

Results of immunotherapies in sarcomas, specifically those based on immune checkpoint inhibitors, have been inconsistent across studies (table 2).

It is difficult to compare these different trials as they included different subtypes.

Nevertheless, the ORR achieved by single agents in all these trials was < 20%.

Combinations should be investigated.

However, it is clear that patients with certain sarcoma subtypes responded and we need to pursue the early leads in activity found in these histotypes.

Translational researches from biopsy specimens, blood, and stool collected from the current study and other studies will help to understand the sarcoma immune microenvironment, and characterise the determinants of response immunotherapy in sarcoma. 

To date, in the absence of predictive biomarker for check point inhibitors, we should select by histology.

Table 2: Immunotherapy studies in soft-tissue sarcoma. SS = synovial sarcoma; UPS = undifferentiated pleomorphic sarcoma; LPS = liposarcoma; ASPS = alveolar soft-part sarcoma; NA = not applicable; Nivo= Nivolumab, Ipi= Ipilimumab.

Trabectedin/durvalumab Combo in unselected population of soft tissue sarcoma

Safety and preliminary efficacy analysis of trabectedin combined with the PDL1 inhibitor durvalumab in a cohort of 16 patients with unresectable or metastatic soft tissue sarcomas treated in phase phase Ib TRAMUNE trial; NCT03085225, were reported.

This trial followed a conventional 3 3 design for the dose escalation phase and included two dose-expansion cohorts; soft tissue sarcomas and ovarian cancer.

3 doses of Trabectedin (1 mg/m²; 1.2mg/m²; 1.5mg/m²) given in combination with Durvalumab (fixed dose 1120 mg on day 2 of each cycle, every three weeks) have been investigated in the dose escalation phase.

Baseline characteristics showed a median patient age of 57 years (25-75) in the soft tissue sarcoma expansion cohort, predominantly female.

Only 1 dose-limiting toxicities (DLT) was observed at the level 2 dose from the dose-escalation phase of the study.

The DLT was grade 4 hepatic cytolysis and was observed on day 8 of cycle 1.

The dose-expansion phase identified the maximum tolerated dose (MTD) of trabectedin to be 1.2 mg/m2 given over 3 hours on day 1 of each cycle every 3 weeks.
After a median follow-up of 10.7 months, 16 patients were assessable for safety and 14 for efficacy.

Most frequent TRAEs were grade 1-2 nausea and fatigue.

The most common grade 3-4 AE were hepatic cytolysis and neutropenia, as expected.

There were 2 grade 5 AE including multi-organ failure and febrile aplasia.

Treatment interruption due to toxicity was reported in 22% in the phase I and 31% in the phase II.

In terms of efficacy, 6 patients (42.9%) experienced tumor shrinkage, resulting in one partial response (leiomyosarcoma) (ORR = 7.1%; CI95%: 0.2 - 33.9).

8 patients had stable disease.

The 6-month PFR was 28.6% (CI95%: 8.4 - 58.1), and the median PFS was 2.3 months (95% CI 0.8-10.8).

Expression of immune markers PDL1, CD8, and CD163 on baseline has been assessed.

The results showed, low expression of PD-L1 and CD 8. CD8 and CD163 correlated with cell density as well as PFS.

When co-staining of CD163 and CD8 was carried out, investigators noticed 3 clusters of markers, including immune desert tumors, those high in CD163, and those high in CD8.

CD8 high/CD163 low tumor profile at baseline was associated with longer PFS.

Further results from exploratory analysis of immune biomarkers, liquid biopsies, metabolomics on plasma sample are waited.

Considering the design of the study, which required at least one objective response to consider the combination active, the study was overall positive.

The lack of higher activity may be due to the scheduling of the two agents.

Trabectedin was used at lower dose (1.2 mg/m2) than the activity threshold, the infusion period was of 3 hours, and the use or not of steroids was not entirely clear.

Also, the combination resulted in significant toxicities that can prevent higher efficacy.

There is a substantial background for the combination of Trabectedin and anti PD1/PDL1 agents, however due to the safety profile, the development of this combination may be difficult.

Higher efficacy and favorable toxicity profile may require other scheduling and selected population.

Bone sarcoma

Two presentations of promising novel therapies in patients with recurrent Ewing sarcoma, a population with limited or no treatment options, are selected.

New agent for Ewing sarcoma: Anti-ETS agent TK216

TK216 is the first agent to target ETS oncoproteins.

Data from first-in-human phase I study of TK216 in recurrent/refractory Ewing sarcoma were presented.

Eligible patients included adults and children > 10 years, PS ≤ 2, life expectancy of at least 3 months, and adequate cardiac function.

TK216 was administered by continuous intravenous infusion. 200 mg/m2/d was established as the recommended phase II dose (RP2D).

Patients received 200 mg/m2/d for up to 14 days infusion with a 14-day break to complete a cycle.

Vincristine (VCR) could be added to treatment after cycle.

15 patients treated at RP2D were evaluable for response.

2 patients achieved a CR (including one surgical complete response), and 5 had stable disease.

The disease control rate (CR PR SD) was of 47%.

Treatment were manageable consisting of transient marrow suppression (neutropenia/febrile neutropenia, thrombocytopenia, anemia) and fatigue.

No new toxicities were noted except neurotoxicity due to VCR.

TK216 is very early in development, more investigations are warranted to achieve better understanding of the mechanism of response and non-response, activity by translocation partners, and by disease stage.

It is probably the first step for treatments that target transcription factors.

Extension for other cancer types that contain related fusion proteins as a result of similar chromosomal translocations is possible.

Regorafenib: signals of benefit for patients with recurrent and refractory Ewing sarcoma

REGOBONE is non-comparative phase II, double-blind, placebo-controlled trial designed to evaluate the activity and safety of regorafenib in 5 independent cohorts of different bone sarcoma.

Results from bone Ewing sarcoma cohort were presented during the proffered paper session.

Patients with recurrent bone Ewing sarcomas not amenable to curative strategy, ≥10 years, ECOG 0-1, and confirmed measurable progressive disease were included.

Patients were randomised (2:1) to receive either regorafenib (160 mg/d, 21/28 d) or matched placebo with optional cross-over. 41 patients were included; median age was 32 (16-59), 28 were men.

36 patients were evaluable for response.

Ten of 13 patients crossed-over to regorafenib after progression. 5 (21.7%) patients receiving regorafenib achieved a partial response.

Median PFS was 11.4 weeks (95%CI 4.6-22.9) versus 3.9 weeks (95% CI 3.3-7.3) in regorafenib and placebo arms, respectively.

Median OS was 34.9 weeks (95% CI 17.6-58.7) and 30.4 weeks (95% CI 10.0- not estimable) for regorafenib and placebo arms, respectively.

These results are consistent with findings from SARC024 trial.

Safety results were consistent with previous findings.

The most common grade 3 or 4 TRAEs during the double-blind period were diarrhea (13%), hand-foot skin reaction (13%), asthenia (9%), thrombocytopenia (9%), mucosal inflammation (9%) and febrile neutropenia (9%).

One toxic death due to thrombocytopenia has been reported.

Although formally negative, a prolonged PFS was observed in patients receiving regorafenib suggesting a clinical benefit in this population with a major unmet need.

Further investigations including combinations studies, maintenance therapy, and correlative biomarkers studies are need to translate these signals of benefit into improved outcome.

Conclusion

Although none of the studies presented 2020 ESMO virtual meeting in the field of sarcoma are revolutionary, valuable data that add important information to the overall picture were presented.

In addition, early phase clinical trials with novel agents such as TK216 in Ewing sarcoma or immunotherapy in soft tissue sarcomas indicate the future directions of drug development in this rare and heterogenous disease.

Key points
Gastrointestinal stromal tumours

• Avapritinib is the new standard of care for unresectable and or metastatic GISTs with PDGFRA D842V mutation.

• Ripretinib given in ≥ 4th line setting continues to provide clinically meaningful benefit for patients with refractory advanced GIST with no emerging safety concerns after additional 9 months follow-up in INVICTUS trial.

• Ripretinib dose escalation to 150 mg BID after progression on 150 mg QD showed an additional PFS benefit, with a favorable safety profile.
Soft tissue sarcomas

• Pembrolizumab shows high levels of prolonged activity in selected subtypes of rare sarcomas, mainly MRT and ASPS.

• The combination of trabectedin and durvalumab yielded limited activity in patients with advanced soft tissue sarcomas with a substantial toxicity.

Bone sarcomas

• Early phase study with a novel agent TK216, designed to bind ETS proteins, showed anti-tumor activity and good tolerability in adult and pediatric patients with relapsed / refractory Ewing sarcomas.

• REGOBONE trial did not meet its primary endpoint in the Ewing sarcoma cohort, however a promising signal of benefit in patients receiving regorafenib is observed.

References:

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