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ESMO Open Feb 2021While the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and...
BACKGROUND
While the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear.
PATIENTS AND METHODS
We analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2).
RESULTS
Complex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10), PDGFB and C levels were lower in GIST (P < 2 × 10 and P < 3 × 10) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis.
CONCLUSIONS
The expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse.
Topics: Humans; Ligands; Liposarcoma, Myxoid; Lymphokines; Neoplasm Recurrence, Local; Platelet-Derived Growth Factor; Prognosis; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Sarcoma
PubMed: 33524869
DOI: 10.1016/j.esmoop.2020.100037 -
MAbs 2017Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend...
Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6-9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US. Brodalumab, was granted a first approval in Japan in July 2016. Regulatory actions on marketing applications for brodalumab in the EU and US are not expected until 2017. In 2017, first EU or US approvals may also be granted for at least nine mAbs (ocrelizumab, avelumab, Xilonix, inotuzumab ozogamicin, dupilumab, sirukumab, sarilumab, guselkumab, romosozumab) that are not yet approved in any country. Based on announcements of company plans for regulatory submissions and the estimated completion dates for late-stage clinical studies, and assuming the study results are positive, marketing applications for at least 6 antibody therapeutics (benralizumab, tildrakizumab, emicizumab, galcanezumab, ibalizumab, PRO-140) that are now being evaluated in late-stage clinical studies may be submitted during December 2016* or 2017. Other 'antibodies to watch' in 2017 include 20 mAbs are undergoing evaluation in pivotal studies that have estimated primary completion dates in late 2016 or during 2017. Of these, 5 mAbs are for cancer (durvalumab, JNJ-56022473, ublituximab, anetumab ravtansine, glembatumumab vedotin) and 15 mAbs are for non-cancer indications (caplacizumab, lanadelumab, roledumab, tralokinumab, risankizumab, SA237, emapalumab, suptavumab, erenumab, eptinezumab, fremanezumab, fasinumab, tanezumab, lampalizumab, brolucizumab). Positive results from these studies may enable submission of marketing applications in 2017 or 2018, or provide justification for additional studies. *See note added in proof for update through December 31, 2016.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Neoplasms; United States
PubMed: 27960628
DOI: 10.1080/19420862.2016.1269580 -
Cell Feb 2017Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA...
Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Approval; Humans; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 28187274
DOI: 10.1016/j.cell.2017.01.028 -
Oncology (Williston Park, N.Y.) Feb 2017The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and... (Review)
Review
The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and immunotherapies. Advances in the understanding of cancer biology and therapeutic strategies have resulted in increasing numbers of new drug applications and approvals. Consequently, practicing oncologists need to learn how the newly available agents function and what toxicities to watch for, as well as ways to optimize the use of both new drugs and previously approved drugs with new indications. In 2016, the US Food and Drug Administration approved three novel drugs for the treatment of solid malignancies-olaratumab in selected patients with soft-tissue sarcoma, atezolizumab for the treatment of bladder cancer, and rucaparib for the treatment of ovarian cancer; also in 2016, the use of previously approved anticancer agents (including atezolizumab) was expanded into 11 new patient populations. The diversity of options for patients is evident in the broad range of the 2016 approvals, which include immune checkpoint inhibitors, targeted therapies, monoclonal antibodies, and traditional cytotoxic agents. This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning.
Topics: Antineoplastic Agents; Drug Approval; Humans; Immunotherapy; Neoplasms
PubMed: 28205191
DOI: No ID Found -
Applied Health Economics and Health... Feb 2020The potential benefits of early patient access to new medicines in areas of high unmet medical need are recognised, but uncertainties concerning effectiveness, safety...
The potential benefits of early patient access to new medicines in areas of high unmet medical need are recognised, but uncertainties concerning effectiveness, safety and added value when new medicines are authorised, and subsequently funded based on initial preliminary data only, have important implications. In 2016 olaratumab received accelerated conditional approval from both the European Medicines Agency and the US Food and Drug Administration for the treatment of soft-tissue sarcoma, based on the claims of a substantial reduction in the risk of death with an 11.8-month improvement in median overall survival in a phase II trial in combination with doxorubicin vs. doxorubicin alone. The failure to confirm these benefits in the post-authorisation pivotal trial has highlighted key concerns regarding early access and conditional approvals for new medicines. Concerns include potentially considerable clinical and economic costs, so that patients may have received suboptimal treatment and any money spent has foregone the opportunity to improve access to effective treatments. As a result, it seems reasonable to reconsider current marketing authorisation models and approaches. Potential pathways forward include closer collaboration between regulators, pharmaceutical companies and payers to enhance the generation of rapid and comparative confirmatory trials in a safe and fair manner, with minimal patient exposure as required to achieve robust evidence. Additionally, it may be time to review early access systems, and to explore new avenues regarding who should pay or part pay for new treatments whilst information is being collected as part of any obligations for conditional marketing authorisation. Greater co-operation between countries regarding the collection of data in routine clinical care, and further research on post-marketing data analysis and interpretation, may also contribute to improved appraisal and continued access to new innovative cancer treatments.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Agents; Doxorubicin; Drug Approval; Europe; Female; Humans; Male; Middle Aged; Neoplasms
PubMed: 31696433
DOI: 10.1007/s40258-019-00527-x -
Cancers Mar 2024The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated....
Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.
The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.
PubMed: 38611000
DOI: 10.3390/cancers16071323 -
Therapeutic Advances in Medical Oncology Aug 2017Soft tissue sarcoma (STS) is a biologically heterogeneous malignancy with over 50 subtypes. Historically, there have been few systemic treatment options for this... (Review)
Review
Soft tissue sarcoma (STS) is a biologically heterogeneous malignancy with over 50 subtypes. Historically, there have been few systemic treatment options for this relatively rare disease. Traditional cytotoxic agents, such as anthracyclines, alkylating agents, and taxanes have limited clinical benefit beyond the first-line setting; across all high-grade STS subtypes, median overall survival remains approximately 12-18 months for advanced metastatic disease. The development of targeted therapies has led to recent US Food and Drug Administration approval of four new treatments for high-grade STS in the advanced metastatic setting. Among these, olaratumab is most notable for its improvement in overall survival for patients with anthracycline-naïve disease. Further progress in STS management will rely on novel trial design, subtype-specific therapies and validation of biomarkers to tailor therapy. Immunotherapy has shown promise as a new, but yet undiscovered frontier in the management of STS.
PubMed: 28794805
DOI: 10.1177/1758834017712963 -
Sarcoma 2018Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US)...
BACKGROUND
Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective.
METHODS
An economic model was constructed to estimate costs and outcomes over patients' lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources.
RESULTS
Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at $105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER).
CONCLUSION
Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above.
PubMed: 29785170
DOI: 10.1155/2018/6703963 -
BMC Cancer Jul 2019Soft tissue sarcoma (STS) comprises a family of rare, heterogeneous tumors of mesenchymal origin. Single-agent doxorubicin remains the first-line standard-of-care...
BACKGROUND
Soft tissue sarcoma (STS) comprises a family of rare, heterogeneous tumors of mesenchymal origin. Single-agent doxorubicin remains the first-line standard-of-care treatment for advanced and inoperable STS, but response rates are only around 15%. In 2016, phase Ib/II clinical trial results reported an overall survival benefit of 11.8 months when combining doxorubicin and the platelet-derived growth factor receptor alpha (PDGFRA)-directed antibody olaratumab compared to doxorubicin alone, without providing a scientific rationale for such unprecedented therapeutic effect. We decided to evaluate the efficacy of olaratumab in a panel of STS patient-derived xenografts (PDX).
METHODS
NMRI nu/nu mice were bilaterally transplanted with tumor tissue of patient-derived xenograft models expressing PDGFRA, including models of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (UZLX-STS39), myxofibrosarcoma (UZLX-STS59) and undifferentiated pleomorphic sarcoma (UZLX-STS84). Mice were randomly divided into four different treatment groups: (1) control, (2) doxorubicin (3 mg/kg once weekly), (3) anti-PDGFRA [olaratumab (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of doxorubicin and anti-PDGFRA (same dose/schedule as in the single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy.
RESULTS
Anti-PDGFRA treatment as a single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining doxorubicin and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in UZLX-STS39 and -STS59. A pro-apoptotic effect was observed in all models except UZLX-STS22. Antitumor effects on histology were not significantly different comparing doxorubicin and the combination treatment. Moreover, anti-PDGFRA treatment, both as a single agent as well as combined with doxorubicin, did not result in inhibition of the downstream MAPK and PI3K/AKT signaling pathways.
CONCLUSIONS
We were not able to demonstrate significant antitumor effects of anti-PDGFRA treatment in selected STS PDX models, neither alone nor in combination with doxorubicin. This is in line with the very recent results of the phase III clinical trial NCT02451943 ANNOUNCE, which did not confirm the clinical benefit of olaratumab in combination with doxorubicin over single agent doxorubicin.
Topics: Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Cell Proliferation; Disease Models, Animal; Doxorubicin; Drug Therapy, Combination; Female; Heterografts; Humans; Male; Mice; Mice, Nude; Middle Aged; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 31331295
DOI: 10.1186/s12885-019-5872-1 -
Translational Oncology Sep 2019Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of...
Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.
PubMed: 31299622
DOI: 10.1016/j.tranon.2019.06.002