ASH 2024 | COALITION: glofitamab-R-CHOP or glofitamab-pola-R-CHP in younger patients with high-risk LBCL

So the COALITION study was an investigator-initiated trial run in 15 sites in Australia where we were looking at the combination of the CD20 CD3 bispecific antibody glofitimab in combination with two chemotherapy backbones either R-CHOP or pola-R-CHP. In this study we really wanted to focus on high-risk patients that are at risk of treatment failure with your standard regimens of R-CHOP or pola-R-CHP. And we were excited by the possibility of incorporating a highly active bispecific antibody into the frontline setting. We made a concerted effort to focus on high-risk patients and we did that in a number of ways. Firstly, our inclusion criteria used a combination of high-risk features including an IPI score of three to five but acknowledging that that does not capture all patients with high-risk disease we also incorporated an NCCN IPI of four or higher and and or the presence of double-hit lymphoma which we know conveys a poor prognosis independent of the IPI scores and we feel that by using this combination of inclusion criteria we were able to capture a very high-risk patient population. We also incorporated some study design elements to help to capture patients who are ordinarily left out of clinical trials because they’re unable to wait for study enrollment procedures. And we allowed patients to come onto the study either before or after a cycle of chemotherapy. In that way, patients with high burden, highly proliferative disease, were able to receive a cycle of chemotherapy quickly and still remain eligible for the study and we found that in fact roughly three-quarters of patients included on our study came on after receiving a cycle of chemotherapy. This enabled our study to have a really short time from diagnosis to first chemotherapy exposure which was 14 days and in fact shortest for those who came on after receiving a cycle of chemotherapy and their median time to treatment was 12 days. We’re pretty confident that we didn’t exclude any patients who had high burden highly proliferative disease this really was borne out in the patient characteristics that we saw. We had a high proportion of patients with very high burden disease. We assessed this using total metabolic tumor volume and the median total metabolic tumor volume was over 800 cubic centimeters we know from previous studies that patients over 200 cubic centimeters have poor outcomes so our patient group have very high tumour burden going into the study. So our study incorporated the two arms with glofitimab and R-CHOP or glofitimab with pola-R-CHP and we had 40 patients in each arm. The glofitimab was added in at cycle two with step-up dosing reaching the full dose during the cycle three of therapy. Patients then went on to receive a total of six induction treatment cycles and then two cycles of glofitimab monotherapy. CNS prophylaxis with methotrexate was allowed at investigator discretion. The results of the study are highly promising. Firstly from the safety perspective we saw no new safety signals adding in the glofitimab to the chemotherapy backbones. The most common side effects were what we would expect with either R-CHOP or pola-R-CHP alone and included neutropenia, peripheral neuropathy, fatigue and GI upset but there were no additional signals of increased infections or febrile neutropenia. From the safety perspective we also found that most patients were able to complete all therapy and there were very few discontinuations. We occasionally had to dose adjust or dose delay patients but this did not result in a reduction of the relative dose intensity and relative dose intensity of all major agents was very high, close to 100% median and more than 90% of patients received more than 90% relative dose intensity for all the major agents in the study. This demonstrated that this is a highly deliverable combination and the addition of glofitimab did not compromise the chemotherapy. The results of the study were also very promising. We saw a complete response rate of 98% in both treatment arms and overall response rate of 100%. What was interesting was that this response rate seemed to evolve over time. And while most patients achieved a CR, at the end of induction treatment, which corresponds to the completion of R-CHOP or pola-R-CHP, the complete response rate was significantly lower at 70% with glofit-R-CHOP and 80% with pola-R-CHP. And that means that a significant proportion of patients actually had a partial response by PET criteria at the end of the induction treatment. But all of these patients went on to achieve a subsequent complete response, and none of these patients has progressed. This was interesting to us and indicated that PET may not be the best marker of disease activity when we incorporate a bispecific antibody into the frontline setting. We saw this in a number of the PET scans of our own patients where small sites of FDG avidity may remain at sites of original bulky disease but that these resolved over time either after the two further cycles of glofitimab or just during the follow-up phase. This was really supported by the cell-free DNA assessment and we had 88% of patients MRD negative by cell-free DNA at the end of treatment including a significant proportion of those in a partial response. So really indicating to us that the depth of response was more significant than the PET scans at the end of treatment may suggest. In terms of the durability of the response this was also very promising. At 12 months the progression-free survival was over 90% in the pola-R-CHP arm and close to 90% percent in the R-CHOP arm and at two years the progression-free survival was 86 percent in both arms. This compares very favorably to the results in similar patient populations with either R-CHOP or pola-R-CHP alone. So we’re excited by the results of this study and we look forward to the global randomized studies incorporating glofitamab into the front line. One of the issues with the big randomized studies however is that they tend to include more patients with favourable risk characteristics and those patients may, it may be more difficult to show an improvement in those more favourable risk patient populations and we therefore think that our study provides really important information particularly for the highest risk patients that we treat.

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