Feature article

New Care Pathways with Immunotherapy and Radiation Therapy in Development for Personalized Care

New data showing radiotherapy (RT) can convert a patient's own tumor into an in situ vaccine has produced considerable interest in testing RT in combination with immunotherapy.Significant advancements in immunotherapies suggest this therapeutic combination could foster even greater efficacy.If oncologists are able to immediately determine that a patient will be more responsive to a combination therapy compared to a monotherapy, the patient can avoid spending time trying various treatments unsuccessfully while their cancer progresses.3

Today, hundreds of cancer drugs are tested alone while state-of-the-art cancer therapy is frequently multimodal--it combines radiation and drugs.2 Radiotherapy is unique as a partner for combination treatments given it is readily available, unrestricted by patent rights, and part of the standard of care for almost every type of cancer.1

Researchers believe the timing is ripe for increasing the number of clinical trials that test promising new immunotherapy in combination with radiation earlier in the drug development cycle.2 This is an essential step in identifying more opportunities for increasing cancer cure rates for a greater proportion of patients before they develop metastatic disease.2

Personalization of radiotherapy

In radiation oncology, the standard delivery of a dose of radiotherapy is highly personalized.Radiation dose determination takes into account the specific size, shape, and anatomy of each recipient, as well as the unique position of cancerous tissue so that each treatment is uniquely designed for that patient from a geometric, geographic, and physical point of view.4

Successful personalized immunization of cancer patients with local tumor irradiation could provide a simple, widely available, and cost-effective means to enhance responses to immunotherapy.In most patients, blocking immunosuppression is ineffective without a treatment that induces de novo anti-tumor immune responses.1Evidence that T-cells recognize unique mutation-generated neoantigens in patients responding to immunotherapy implies that a tumor vaccine needs to be highly personalized.1

From a biological point of view, combining radiation with immunotherapy has further enhanced the personalized nature of radiotherapy.In fact, by eliciting an anti-tumor immune response that is specific to an individual cancer, radiotherapy combined with immunotherapy, i.e., immune checkpoint inhibitors, rises to the role of personalized medicine.4

Preclinical and clinical data have increased the number of prospective trials investigating the combination of immunotherapy and RT with current estimates of at least 80 ongoing studies.Researchers are looking at the addition of immunotherapy to radiation standard-of-care approach, the addition of radiation to immunotherapy standard-of-care, or exploration of the synergy observed in preclinical models.5

Lung cancer combination therapy improves survival

As the number of patients receiving immunogenic treatment for cancer grows, the combination of radiation and immunotherapy has become increasingly relevant in the palliative care setting.In the case of non-small-cell lung cancer (NSCLC), a subset of patient data from a recent clinical trial suggests immunotherapy may be particularly effective when administered after radiation.Patients participating in the trial who had received radiation treatment before the study began fared better than those who had never received radiation before taking the study medication.A separate, subset analysis of those patients showed that more than 40 percent were able to continue using the trial drug for a median of 179 days following palliative radiation treatment.5

An objective response rate of 33 percent was found in a separate prospective study of 40 chemotherapy-refractory patients with metastatic NSCLC.The response rate was identified among those patients completing four cycles of immunotherapy treatment and a course of three to five fractions of radiation to one metastasis.Survival rate was found to be significantly better with many patients remaining alive with controlled disease.4

Brain cancer methylation status key to combination therapy outcomes

Glioblastoma patients typically have a poor prognosis and few treatment options due to tumor cell heterogeneity, incomplete surgical resection, blood-brain barrier challenges, and the risk of swelling from chemotherapy side effects.While median survival has increased from 10 to 20 months over the past two decades, and current treatments can slow disease progression, they rarely provide a cure or the outcomes oncologists wish to offer patients.

Recent safety and tolerability data updates from two exploratory cohorts of newly diagnosed glioblastoma patients that received combination immunotherapy plus standard RT, with or without chemotherapy, support additional development for this disease.Treatment was found to be well tolerated with the incidence of high-grade neurological adverse events (AE) consistent with those previously reported in glioblastoma.Addition of the chemotherapy drug was not associated with any significant additional AEs other than those found when it is used alone.6

Because methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene that produces carcinogenic guanine mutations in DNA has been linked to improved outcomes when chemotherapy is added to RT, patients were assigned to study groups based on methylation status.6 The first group included 55 study participants total, 12 patients with methylated MGMT and 43 with unmethylated MGMT. The second group, which had 58 participants, only included those with unmethylated MGMT.6

Combination therapy that included immunotherapeutic agents, RT, and chemotherapy was given to the first group, the one that included patients with either methylated and unmethylated MGMT.6 Immunotherapy was given at 3 mg/kg once every two weeks plus standard RT.6 Chemotherapy was given concurrently at 75 mg/m2 daily. Additional chemotherapy was administered as follow-up at 150 to 200 mg/m2 for five days in a 28-day cycle for at least six or more cycles.6 The 58 patients in the group with unmethylated MGMT were given the same dose of immunotherapy and standard RT but did not receive chemotherapy.6

Earlier stage 'cold' tumor lung cancer may benefit

Failure of a recent phase III trial investigating prostate cancer highlights not only the continued challenges, but also new opportunities for combining immunotherapy with RT in cold-tumor cancers known for their poor response to immunotherapy alone.7 When immunotherapy was added to palliative RT in heavily pre-treated low-testosterone metastatic prostate cancer patients researchers did not observe an overall survival benefit, however, a progression-free survival benefit was found.7 Investigators conducted further data analysis that showed a survival benefit was experienced by a subset of these patients who had less advanced metastatic prostate cancer.7 Additional in-depth studies are recommended to determine the efficacy of combination immunotherapy and RT with earlier stage cold tumor cancers.7

Multi-site advanced solid tumors show improvement

Improved outcomes for patients with advanced solid tumors and multiple metastatic sites were reported by the first and largest prospective trial investigating the safety of multi-site ablative stereotactic body radiotherapy (SBRT) combined with immunotherapy.8 Ovarian/fallopian tube, NSCLC, breast, cholangiocarcinoma, and endometrial were the primary cancers included in the trial with results demonstrating the administration of SBRT before immunotherapy was well tolerated.8

The trial enrolled 79 patients (although only 73 were included in the final analysis) with metastatic solid tumors who experienced disease progression while on standard treatment.8 Study participants were considered heavily pre-treated with a median number of five prior therapies.8 Investigators used the Response Evaluation Criteria in Solid Tumors (RECIST) to determine measurable disease and also confirmed the presence of SBRT-responsive metastases.8

Two to four metastases were chosen for each patient resulting in almost 95 percent of patients receiving SBRT on at least two sites.8 Researchers reported 76 patients received SBRT for a total of 151 metastases irradiated.8 Metastatic tumor locations included 30 in the peripheral lung, 23 in the central lung, 28 in the abdomen/pelvis, and 24 in the liver.8 Other metastatic sites that were treated less frequently include bone (16), mediastinal/thoracic (15), and the spine (15).8 At least one cycle of immunotherapy was initiated within seven days after the final SBRT treatment for 73 patients.8

Imaging follow-up was conducted on 68 patients revealing an overall objective response rate of 13.2 percent.8 Irradiated lesions experienced a mean tumor diameter change was –21.7 percent compared with 1.7 percent for non-irradiated lesions.8 The abscopal response was present in 26.9 percent of patients where the reduction in any single non-irradiated measurable lesion was defined as 30 percent.8

Gut microbiome key biomarker for immunotherapy efficacy 

One key clinical biomarker and treatment target for determining immunotherapy efficacy that is growing in significance is the gut microbiome.7 During a recent medical session, preclinical data was presented that demonstrates the potential for antibiotics targeting gram-positive gut microbiota to increase the anti-tumor impact of RT.7 Researchers used human tumor cell models of melanoma, cervical carcinoma, and lung carcinoma transplanted into mice for observation.7 Interferon-γ-expressing CD8+ T-cells that are part of the adaptive immune response were found to facilitate the observed anti-tumor effects of combination therapy while CD103+ dendritic cells, or the messengers between adaptive and innate immune response, also improved their ability to cross-present tumor antigen at an increased frequency.7

What's next

Researchers are excited about the potential of combination RT and immunotherapy to transform cancer treatment by harnessing the immune system in synergistic approaches.Although critical progress and evidence supporting these therapeutic pathways are accumulating, robust clinical data from ongoing trials are warranted in order to determine safety and efficacy.7

Well-designed, prospective trials are also needed to answer essential RT questions about optimal dose/fractionation, technique, target site/volume, and sequencing with immunotherapies.Understanding molecular, genetic and immunologic mechanisms that dictate the immunomodulatory effects of radiotherapy will be critical to the most successful combinations.Ultimately, the development of biomarkers to predict treatment response to immunotherapies will help identify patients most likely to benefit from a specific combination treatment.9

 

References

  1. Radiotherapy: Changing the Game in Immunotherapy. Cell. https://www.cell.com/trends/cancer/abstract/S2405-8033(16)30036-X Accessed 9/9/2018
  2. More clinical trials should combine radiation therapy with promising new cancer drugs. ASTRO https://www.astro.org/News-and-Publications/News-and-Media-Center/News-Releases/2018/More-clinical-trials-should-combine-radiation-ther Accessed 9/9/2018
  3. Challenges, Trends and Opportunities for Personalized Medicine in Oncology. R&D Magazine. https://www.rdmag.com/article/2015/12/challenges-trends-and-opportunities-personalized-medicine-oncology Accessed 9/9/2018
  4. Abscopal Responses in Metastatic Non-Small Cell Lung Cancer (NSCLC) Patients Treated on a Phase 2 Study of Combined Radiation Therapy and Ipilimumab: Evidence for the In Situ Vaccination Hypothesis of Radiation. International Journal of Radiation Oncology. https://www.redjournal.org/article/S0360-3016(15)00890-1/abstract Accessed 9/5/2018
  5. Combining Immunotherapy and Radiotherapy Shows Good Synergy. http://www.personalizedmedonc.com/article/combining-immunotherapy-and-radiotherapy-shows-good-synergy/ Accessed 9/9/2018
  6. Updated safety results from CheckMate 143 support further study in patients with newly diagnosed glioblastoma. ESMO European Society for Medical Oncology. https://www.esmo.org/Oncology-News/Combined-Nivolumab-and-Radiotherapy-Temozolomide-Is-Safe-in-Patients-With-Newly-Diagnosed-Glioblastoma Accessed 9/5/2018
  7. Incorporating Radiation Oncology into Immunotherapy: proceedings from the ASTRO-SITC-NCI immunotherapy workshop. Journal for Immunotherapy of Cancer. https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0317-y Accessed 9/9/2018
  8. Combination Radiotherapy and Immunotherapy Appears Safe and Clinically Active in Advanced Solid Tumors. The ASCO Post. http://www.ascopost.com/issues/february-25-2018/combination-radiotherapy-and-immunotherapy-appears-safe-and-clinically-active-in-advanced-solid-tumors/ Accessed 9/5/2018
  9. Current clinical trials testing the combination of immunotherapy with radiotherapy. Journal for ImmunoTherapy of Cancer. https://jitc.biomedcentral.com/articles/10.1186/s40425-016-0156-7 Accessed 9/9/2018