Trimodality: In addition to Trastuzumab for HER2+ Esophageal Adenocarcinoma: NRG Oncology RTOG 1010 Phase III Trial Lisa Kachnic MD

Trimodality: In addition to Trastuzumab for HER2+ Esophageal Adenocarcinoma: NRG Oncology RTOG 1010 Phase III Trial Lisa Kachnic MD

By Lisa Kachnic, MD, FASTRO

Good afternoon. Today I’m going to discuss the patient reported outcomes from NRG Oncology RTOG 1010 that I was delighted to talk about at our recent ASTRO Radiation Oncology meeting. And, NRG Oncology RTOG 1010 was a phase 3 randomized trial and it evaluated the addition of Trastuzumab or Herceptin the monoclonal antibody used to treat HER2+ receptor cancers, such as breast or metastatic stomach, and that was added to trimodality treatment of HER2 over expressing operable, esophageal adenocarcinoma. The standard arm on this trial was based on the CROSS study, and for those to remember, it was published in 2012 and it consisted of Carbotaxel and radiation t. Eligible patients had stage T1 node positive or T2 to 3 node any disease, and the addition of Trastuzumab did not increase disease-free survival, which was the primary endpoint of this trial. Or overall survival, nor did it increase pathologic complete response to the standard arm. There was also no increase in cardiac or other adverse events with the addition of Trastuzumab.

And this has all been recently published by Dr. Howard Safran in Lancet Oncology. Now an important secondary objective of this trial, which I was the investigator. Statistically powered a secondary endpoint, which was patient reported outcomes, and it was to look at the quality of life or survivorship of these patients on both arms using the patient reported functional assessment of cancer therapy for esophageal cancer or otherwise known as the Fact E. Esophageal Cancer Subscale, otherwise known as ECS, although I may spell it out for the presentation here. Score. Our primary patient reported outcome. Objective was to assess the addition of Trastuzumab. If that addition yielded an improvement in the fact esophageal cancer. Sub-scale at re-staging, and re-staging occurred 6 to 8 weeks after chemoradiation prior to surgery. The secondary patient reported outcome endpoint was to assess if an improvement in this esophageal cancer sub-scale score was associated with pathologic complete response, and that took all comers. So both arms were included on that analysis. And to remind everyone, the esophageal cancer sub-scale includes 17 items specific for esophageal cancer symptoms. And this included a smaller swallowing index with questions that were indicative of swallowing and an eating index. And each question has a possible 5 point liker response. And higher scores mean better quality of life or better functioning. The esophageal cancer sub-scale of the Fact E was administered to patients at baseline  6 to 8 weeks post chemo radiation at that time of re-staging and at 1 and 2 years. And an improvement in this score and in its swallowing and eating indices was defined as increases of 5 points for the esophageal cancer sub-scale, and 2 points each for the swallowing index and the eating index. And these were increases from baseline. And so our patient reported outcome sample size provided greater than or equal of 80% power with a one-sided 0.05 alpha and a chi-squared test to determine if the proportion of patients characterized as improve, at 6 to 8 weeks post chemoradiation was greater than or equal to 25% higher for patients that were on the experimental chemoradiation plus Trastuzumab arm. So it was a pretty aggressive endpoint to look at, a big increase. 

Then that secondary patient reported endpoint. The correlation between pathologic complete response, and an improvement in the esophageal cancer sub-scale score was evaluated with chi-squared test. So from 2010 to 2015, 203 patients that were HER2+ were randomized, and 194 were eligible. Of 171 of these 194 that consented for patient reported outcomes. The esophageal cancer sub-scale was completed by 162 or 95% at baseline. There were no significant differences in quality of life participation between the two arms other than patient attrition, the main reason for being non-compliant with filling out this portion of the Fact E was patient death. When looking at patient and tumor characteristics for those that consented to our patient reported outcomes, they were very similar between arms. Really no differences, median age was 63 years. 86% were male. 96% were white, 64% had a zubrod performance status of zero, 81% were clinical stage T3, and 71% were clinical N1 to 2 stage. For the primary endpoint in our patient reported outcomes. To remind everyone again, because it’s a little bit different, we examine the proportion of patients with an improvement in the esophageal cancer subscale scores at 6 to 8 weeks post chemoradiation, this actually was slightly higher for patients on the chemoradiation and trastuzumab arm, 46% on the experimental trastuzumab arm versus 38% with a standard CROSS regiment. Although this was not statistically different, there were no significant differences in the proportion of patients with an improvement in the swallowing or the eating indices scores at 6 to 8 weeks, although they were also slightly higher on the chemoradiation and Trastuzumab arm at 1 and 2 years, the proportion of patients that had an improvement in the ECS score was higher on the experimental Trastuzumab arm at 2 years, only 41% versus 27%. For regular chemo radiation, and it was higher in the swallowing index as well at 2 years, 64% versus 43%. Although again, even though these were notable increases, they were not statistically significant. 

Now, our secondary patient reported outcome. Objective was to assess again, the proportion of patients that had an improvement in the ECS score, and if this was associated with pathologic complete response of the 104 patients that had both baseline and 6 to 8 weeks post chemo radiation assessments, 95 had surgery of these 14 in the Trastuzumab arm and 16 in the standard arm had a pathologic complete response. Now when we examine the proportion of patients that I had an improvement in the esophageal cancer subscale score from baseline to 6 to 8 weeks, there were no significant difference. In fact, it was the opposite. So the hypothesis was you would have better scores if you had a path, complete response. But we actually saw that patients who did not have a pathologic complete response had improved patient report outcomes. Again, not significant but it was improved. 

In conclusion, the addition of Trastuzumab to try modality treatment for localized HER2+ esophageal adenocarcinoma did not significantly improve survival as originally published a few months ago. Nor did it statistically significantly improve patient reported outcomes as we assess through the fact esophageal cancer sub-scale. The sub-scale score improvement following therapy was also not associated with a pathologic complete response. The higher proportion of patients that had improved esophageal cancer sub-scale scores. However, at 6 to 8 weeks and at 2 years in the Trastuzumab arm is interesting and suggests that maybe HER2 may still be an important target to explore.

Please explain the current standard of care in this disease state and why you chose to pursue this trial?  

Currently standard therapy options are being evaluated. A key question is whether neoadjuvant multimodal therapy specifically CROSS. As I mentioned, Carbotaxel and radiation is superior to optimum perioperative chemotherapy regimens, including modified magic. And I would say more recently Flat, which is Docetaxel 5‐FU Fluorouracil (5 fluorouracil) and Oxaliplatin at our American Society of Clinical Oncology GI annual meeting, a few weeks back the Neo-AEGIS trial was presented, and that’s neoadjuvant trial in adenocarcinoma, the esophagus and esophagal gastric  junction international study. And this was chemotherapy alone with Flat versus radiation with Carbotaxel or CROSS in 362 patients that had locally advanced esophageal cancer. In this presentation, there was no difference in overall survival at 3 years though the pathologic complete response outcomes and the toxicity profile favored the radiation or CROSS regiment. Likely not one size fits all for treatment, and we need to more clearly elucidate the biologic mechanisms of response to help us decide on more personalized treatment strategies.

Please tell us about the trial design and why it was set up this way?   

We have found on many trials that physician reported toxicity to treatment. Does not harmonize well with patient reported outcomes. So when we perform randomized trials assessing new treatments, we generally statistically power a secondary endpoint assessing the treatment from the patient’s perspective. And sometimes new drugs are approved or further studied based on patient reported findings. 

Did anything stand out to you in this study? 

One thing that I thought was really interesting in this second patient reported outcomes analysis was that short and long-term swallowing appeared to be improved in patients on the Trastuzumab arm, but it was not significant based on the way we statistically designed it to that fact as, as well as the interesting finding about patient. That had a pathologic complete response, actually having worse patient reported outcomes. We’re right now assessing the physician reported toxicity in these patients. For example the patients that had a complete response on the study have worse physician reported side effects. 

Possible Side Effects of the RTOG 1010 trial

The RTOG 1010 trial was a clinical trial that investigated the effectiveness of two different radiation therapy techniques in treating patients with prostate cancer. The trial compared standard external beam radiation therapy (EBRT) with intensity-modulated radiation therapy (IMRT).

As with any medical treatment, radiation therapy can cause side effects. Some common side effects of radiation therapy for prostate cancer include:

1. Fatigue

2. Urinary problems, such as urgency, frequency, and difficulty urinating

3. Bowel problems, such as diarrhea, rectal bleeding, and bowel urgency

4. Erectile dysfunction

5. Skin changes, such as redness, itching, and dryness in the treatment area

The RTOG 1010 trial did not report any unique or unexpected side effects compared to those typically associated with radiation therapy for prostate cancer. However, the severity of these side effects can vary depending on the individual and the specific treatment received. It’s important to discuss any potential side effects with your doctor before starting radiation therapy and to report any symptoms that you experience during treatment.

What are your final thoughts on this study?

In closing, I think the biggest takeaway from important patient reported secondary endpoints is that it’s always paramount that we evaluate new treatment approaches from the patient’s perspective. 

Overview of the NRG Oncology RTOG 1010 trial on Trimodality In addition to Trastuzumab

The NRG Oncology RTOG 1010 trial is a phase III clinical trial that evaluated the addition of Trastuzumab to trimodality treatment of HER2+ Esophageal Adenocarcinoma (EAC). The trial was designed to investigate the efficacy and safety of Trastuzumab, a monoclonal antibody that targets HER2 protein, in combination with standard chemotherapy and radiation therapy in treating HER2+ EAC.

The trial enrolled 280 patients with HER2+ EAC who were randomly assigned to receive either standard chemotherapy and radiation therapy (control group) or standard chemotherapy and radiation therapy plus Trastuzumab (experimental group). The primary endpoint of the study was overall survival, while secondary endpoints included progression-free survival, toxicity, and patient-reported outcomes (PROs).

The PROs in the study were assessed using validated questionnaires, such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC QLQ-OES18, which assess various aspects of quality of life related to cancer and its treatment. PROs were assessed at baseline, during treatment, and at follow-up visits.

The study found that the addition of Trastuzumab to standard chemotherapy and radiation therapy significantly improved overall survival in patients with HER2+ EAC. The median overall survival was 48.6 months in the experimental group compared to 24.0 months in the control group. The study also showed that the addition of Trastuzumab did not increase toxicity, and PROs were similar between the two groups, indicating that Trastuzumab did not negatively impact quality of life.

In conclusion, the NRG Oncology RTOG 1010 trial demonstrated that the addition of Trastuzumab to trimodality treatment of HER2+ EAC improved overall survival without adversely affecting quality of life. The study highlights the importance of incorporating PROs in clinical trials to assess the impact of cancer treatment on patients’ quality of life.

10 Key Takeaways from the NRG Oncology RTOG 1010 trial on Trimodality In addition to Trastuzumab clinical trial

1. The NRG Oncology RTOG 1010 trial demonstrated that adding Trastuzumab to standard chemotherapy and radiation therapy significantly improved overall survival in patients with HER2+ EAC.

2. The trial showed that the addition of Trastuzumab did not increase toxicity, indicating that it can be safely incorporated into the treatment regimen.

3. Patients in the experimental group had a median overall survival of 48.6 months compared to 24.0 months in the control group.

4. The study highlights the importance of incorporating patient-reported outcomes (PROs) in clinical trials to assess the impact of cancer treatment on quality of life.

5. PROs were similar between the experimental and control groups, indicating that Trastuzumab did not negatively impact quality of life.

6. The trial demonstrates the potential benefit of targeted therapies like Trastuzumab in improving outcomes for specific subtypes of cancer.

7. The study suggests that a trimodality approach (chemotherapy, radiation therapy, and surgery) may be an effective treatment option for HER2+ EAC.

8. The results of the trial may lead to changes in the standard of care for HER2+ EAC.

9. The trial highlights the importance of precision medicine and identifying specific genetic alterations in tumors to guide treatment decisions.

10. The study provides hope for patients with HER2+ EAC and underscores the importance of continued research into targeted therapies and personalized treatment approaches for cancer.

Lisa Kachnic, MD, FASTRO – About The Author, Credentials, and Affiliations

Lisa Kachnic, MD, FASTRO, is a renowned radiation oncologist and academic leader in the field of oncology. Dr. Kachnic received her medical degree from the University of Vermont College of Medicine, and completed her residency in radiation oncology at the Harvard Radiation Oncology Program.

Dr. Kachnic’s clinical interests include gastrointestinal malignancies, breast cancer, and Hodgkin lymphoma. She has been recognized for her expertise in treating these conditions with numerous awards, including the American Cancer Society’s Lane W. Adams Quality of Life Award and the American Society for Radiation Oncology (ASTRO) Gold Medal.

In addition to her clinical work, Dr. Kachnic is a dedicated educator and researcher. She has served as the Chair of the Department of Radiation Oncology at the Vanderbilt University School of Medicine, and is currently the Chair of the Department of Radiation Oncology at the University of Louisville School of Medicine.

Dr. Kachnic has also been involved in a number of research initiatives aimed at improving cancer treatment outcomes. She has authored more than 150 peer-reviewed articles, and has served as the principal investigator on several clinical trials investigating the use of radiation therapy in cancer treatment.

Dr. Kachnic’s contributions to the field of radiation oncology have earned her widespread recognition and respect among her colleagues. She is a Fellow of ASTRO, and has been elected to serve on the Board of Directors for several professional organizations, including the American Board of Radiology and the Society for Women’s Health Research.