Until recently, advances in the treatment of soft tissue sarcomas (STS) have been frustratingly slow, largely because of their rarity—sarcomas account for only 1% of adult cancers—and their heterogeneity. These malignancies arise from distinct mesenchymal tissues, each with unique histologic subtypes.
A better understanding of tumor biology and differences across histologies is now fueling substantial progress in novel strategies leveraging immunotherapy, cellular therapy, targeted therapy, and chemotherapy, which was described during the Education Session “The Current Landscape of Early Drug Development for Patients With Sarcoma,” on June 3.
Dr. Vicki L. Keedy speaks during the Education Session “The Current Landscape of Early Drug Development for Patients With Sarcoma.”
Early-Phase Trials for Patients With Sarcoma
As described by Vicki Leigh Keedy, MD, MSCI, of the Vanderbilt University Medical Center, few new drugs for STS were developed during a 45-year period. Given the need for good therapies to offer patients, Dr. Keedy asserted that phase I trials may well be a sarcoma specialist’s “best friend.”
She said that although new discoveries regarding the biology of sarcoma are occurring at a historic pace, novel drug development in this rare cancer is complicated by the heterogeneous nature of disease. Some of these discoveries have led to a few indications in very rare disease subsets, with the approvals based on relatively small phase II trials. But progress is still slow compared with other malignancies. Unlike in other cancers, precision medicine and next-generation sequencing fall short in identifying targetable mutations in sarcoma. As Dr. Keedy noted, “Only in the rare patient do we actually find that true hit that allows us to find either off-label use of a drug or a directed clinical trial.”
So how does the field speed up drug development in sarcoma? Dr. Keedy offered several suggestions for the design of phase I trials:
- Do not include molecular or disease-specific inclusion criteria in first-in-human or dose-escalation trials in order to identify rare, unexpected responders.
- Expansion cohorts within phase Ib studies of targeted agents should focus on validating the biomarker of interest and gathering early efficacy information.
- Molecular characteristics of responders need to be retrospectively analyzed to inform further studies.
- Basket trials should not be confined to the few most common diseases. If the drug targets are truly disease agnostic—a premise of the basket approach—then any patient with a specific driver mutation, including those with sarcoma, should be included.
- Researchers should consider adaptive phase I expansion cohorts, with a plan to move directly into a randomized phase II analysis within the same protocol, whereby the investigational agent is compared with the standard of care.
“With deliberate collaboration, we can leverage these developments to improve drug approvals for our patients with sarcomas,” Dr. Keedy said.
Dr. Breelyn A. Wilky (left) speaks during the Education Session “The Current Landscape of Early Drug Development for Patients With Sarcoma.”
Early-Phase Immunotherapy, Cellular Therapy, and Vaccine Trials
The concept of immunotherapy for sarcoma dates back to the late 1800s when William Coley observed sarcoma regression following severe streptococcal infections. Concerted efforts in this area, however, did not gain traction until the late 20th century. Research undertaken since the early 1980s has included using cytokines as chemotherapy adjuvants, vaccine therapy, and adoptive T-cell therapy—a strategy that continues to be explored and refined for NY-ESO-1 synovial sarcoma with promising outcomes. Most recently, however, the field has seen the dawn of checkpoint inhibitor monotherapy in sarcoma, with positive pembrolizumab data confirming a role for checkpoint inhibitors in some sarcomas.
Immunotherapy has clearly earned a place in the sarcoma armamentarium, according to Breelyn A. Wilky, MD, of the Sylvester Comprehensive Cancer Center. She believes the field is now ready to explore combination immunotherapy strategies to further improve the efficacy of checkpoint inhibitors. However, the trick will be to figure out how best to leverage these modalities in this heterogeneous disease.
“I would argue that in the very near future, our goal should be to arrive at biomarker-driven precision immunotherapy,” Dr. Wilky said.
One of the greatest challenges in successfully implementing immunotherapy in sarcoma is understanding the drivers of the response to immunotherapy. Dr. Wilky explained that the literature to date suggests that predicting a response to immunotherapy in sarcoma will likely be far more complex than identifying a solitary immunohistochemistry biomarker, such as PD-L1.
As with sarcoma histology, the immune environment in different subtypes appears to be quite diverse. Although the majority of STS samples exhibit some degree of immune-cell infiltration, the nature of the infiltrates is not uniform and tends to be skewed toward immunosuppressive cell types. The expression of checkpoint proteins also varies, with PD-L1 expression ranging from 12% to 65% across sarcomas.
Based on these and other findings, Dr. Wilky postulated that, “there may potentially be an immunosignature in some sarcomas. Basically, the immune system is able to recognize the sarcoma as a threat, but it’s running into roadblocks.” Indeed, emerging data suggest that undifferentiated pleomorphic sarcoma and leiomyosarcoma carry a robust immunosignature characterized by activated immune cells, whereas liposarcoma and synovial sarcoma do not.
“I would argue that sarcomas likely lack innate robust immunogenicity and that monotherapy will be insufficient for the majority of sarcomas to induce and sustain immune responses, in contrast to diseases like melanoma,” Dr. Wilky said. This underscores the need for combination approaches to poise checkpoint inhibitors for success in sarcomas.
There is a long list of immunotherapy combinations currently being explored in sarcoma that endeavor to enhance the response to checkpoint inhibitors. These include the addition of vaccines (e.g., CMB 305, a NY-ESO-1 lentivirus vaccine with TLR4 adjuvant), chemotherapy (e.g., doxorubicin, gemcitabine), or radiation therapy to liberate neoantigens so as to better provoke an immune response. Other strategies involve combining targeted therapy with checkpoint inhibitors (e.g., axitinib plus pembrolizumab; imatinib plus ipilimumab), whereas others are employing dual checkpoint inhibitors (e.g., ipilimumab plus nivolumab; durvalumab plus tremelimumab).
Beyond these efforts, Dr. Wilky emphasized that it is important to remember that hundreds of novel targets are being studied in other cancer types. Patients with sarcoma may be eligible to participate in these studies, offering up new avenues of immunotherapy exploration in sarcoma.
Dr. Robin L. Jones speaks during the Education Session “The Current Landscape of Early Drug Development for Patients With Sarcoma.”
Early-Phase Chemotherapy and Targeted Therapy Trials
Although sarcomas constitute only 1% of adult cancers, individuals with this disease represent about 10% of all patients enrolled in phase I trials, underscoring the limited number of therapeutic options for the disease.
So when is the optimal time to consider patients with sarcoma for phase I clinical trials? According to Robin Lewis Jones, MD, BSc, MB, MRCP, of The Royal Marsden NHS Foundation Trust, in the United Kingdom, such decisions are obviously context-dependent and influenced by patient preferences and health status, sarcoma histology, the availability of a trial within a reasonable distance from the patient, and whether there is an open slot in the trial.
However, Dr. Jones said, “I would argue that for patients with relatively challenging-to-treat subtypes it would be good to offer an early-phase clinical trial with a sound biologic rationale.”
To better select the right patients for the right chemotherapy and targeted therapy trials, researchers are now relying more heavily on incorporating putative biomarkers into the design of phase I sarcoma studies as a screening step. A meta-analysis of phase I trials that employed biomarker-based selection suggests that the process of filtering patients can lead to significantly better response rates and progression-free survival. Genomic biomarkers appear to return better results than protein biomarkers, but both approaches excelled over the responses seen when no biomarker was employed to screen patients for trials of targeted therapy.
Dr. Jones pointed out two genomic biomarker-based approaches in sarcoma presented at the 2017 ASCO Annual Meeting (Abstracts 11001 and 11002) that support the rationale for incorporating molecular testing to guide therapy. However, he did note that prospective validation will be needed to confirm the results, which is exactly what the ongoing phase III MULTISARC trial is designed to do.
An impressive array of novel and established agents are currently percolating through early-phase analyses in sarcoma. Some of the most notable targeted therapies under investigation include KIT/PDGFR inhibitors in gastrointestinal stromal tumors, IDH1/2 inhibitors in chondrosarcoma, CDK4/6 or CDK4/MDM2 inhibitors in dedifferentiated liposarcoma, EZH2 inhibitors in epithelioid sarcoma, and NTRK inhibitors in patients with NTRK fusion–positive sarcomas. A number of trials are also evaluating targeted therapy in combination with chemotherapy or radiation therapy and immunotherapy with radiation therapy.
“The major thing to highlight from all of the presentations is that there are many promising agents in development. It’s really important that patients and physicians are aware of these rich opportunities,” Dr. Jones concluded.
–Kara Nyberg, PhD