CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 03, 2023
Expiration: August 02, 2024
Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in FRα-High PROC (MIRASOL): Study Design
Lauren Prescott, MD, MPH:
I would like to switch gears to cover 2 highly anticipated abstracts for ovarian cancer that were presented at ASCO 2023: the MIRASOL and DUO-O trials.
The confirmatory, randomized, phase III MIRASOL trial is evaluating mirvetuximab soravtansine, an ADC, vs investigator’s choice of chemotherapy (eg, either paclitaxel, pegylated ribosomal doxorubicin, or topotecan) in 453 patients with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer and high expression of folate receptor α (FRα) and 1 to 3 previous lines of therapy.10 Patients were randomized to receive mirvetuximab soravtansine 6 mg/kg adjusted ideal body weight every 3 weeks or chemotherapy. The primary endpoint was PFS, and secondary endpoints were ORR by investigator, OS, PROs, safety, DoR, CA-125 response, and time to second PFS interval.
MIRASOL: Baseline Characteristics
Lauren Prescott, MD, MPH:
Approximately 50% of patients had 3 previous lines of chemotherapy. Thus, this was a heavily pretreated patient population. Weekly paclitaxel was the most common comparator arm.
Unlike the phase III SORAYA trial,11 patients in MIRASOL could have been previously treated with bevacizumab but previous bevacizumab was not a requirement. Approximately 55% of patients had previously received a poly (ADP-ribose) polymerase (PARP) inhibitor and all had received prior taxane.
MIRASOL: PFS by Investigator (Primary Endpoint)
Lauren Prescott, MD, MPH:
The primary endpoint of improvement in PFS was met. When compared to investigator’s choice of chemotherapy, mirvetuximab soravtansine significantly prolonged median PFS at 5.6 months (95% CI: 4.34-5.95 months) vs 3.98 months (95% CI: 2.86-4.47 months); HR: 0.65; P <.0001). Although an improvement of 1.62 months in the median PFS may not seem like much, it is important to remember that this is a very difficult disease. Moreover, in the control arm, 50% of patients were already off study at the first disease assessment period due to disease progression compared with 90% of patients remaining on treatment at 6 weeks in the mirvetuximab soravtansine arm.
MIRASOL: Best ORR by Investigator
Lauren Prescott, MD, MPH:
In patients receiving mirvetuximab soravtansine responses were also improved. ORR was 42% (CR: 5%) vs 16% (CR: 0%) with mirvetuximab soravtansine vs the chemotherapy group. This level of response is quite remarkable because in this treatment setting, we mainly talk to patients about palliative-intent chemotherapy.
Mirasol: OS
Lauren Prescott, MD, MPH:
We saw a 4-month OS advantage with mirvetuximab soravtansine compared with chemotherapy with median OS of 16.46 months vs 12.75 months (HR: 0.67; P = .0046). In patients with platinum-resistant ovarian cancer it is very difficult to achieve an OS benefit. Therefore, these results represent a clinically meaningful and statistically significant outcome for our patients.
SORAYA: Outcomes by Prior Bevacizumab
Lauren Prescott, MD, MPH:
Approximately 60% of patients in both arms had previously received bevacizumab. The Kaplan-Meier curves suggest the magnitude of benefit for PFS in the subgroup analyses was comparable regardless of previous bevacizumab use (HR: 0.66 vs 0.64), but there was a trend suggestive of OS benefit in patients who had not previously received bevacizumab (HR: 0.51 vs 0.74).
MIRASOL: Safety Summary
Lauren Prescott, MD, MPH:
It was reassuring to see that there were no new AEs from what was previously described for mirvetuximab soravtansine.11
Overall, 96% and 94% of patients in the mirvetuximab soravtansine arm vs the chemotherapy arm developed treatment-emergent AEs. Grade ≥3 AEs were reported in 24% and 33% of patients in the mirvetuximab soravtansine arm and the chemotherapy arm, respectively. Of importance, treatment discontinuation due to treatment-emergent AES was lower in the mirvetuximab soravtansine arm than the chemotherapy arm (9% vs 16%).
MIRASOL: Selected Treatment-Emergent AEs
Lauren Prescott, MD, MPH:
Overall, hematologic and gastrointestinal treatment-emergent AEs were more common with chemotherapy, whereas ocular AEs were more common with mirvetuximab soravtansine. Of note, ocular and gastrointestinal AEs with mirvetuximab soravtansine were mostly low-grade and highly manageable.
Ritu Salani, MD, MBA:
Having personally used mirvetuximab soravtansine in my patients, I can say that the toxicity profile is well characterized, manageable, and patients can be on this therapy for extended periods of time. Ocular toxicity can be mitigated with the use of eye drops and eye examinations every other cycle, which is not very disruptive to patients and they do very well while on treatment. It is also worth noting that the ocular AE mitigation and management with mirvetuximab is less labor intensive compared with other ADCs like tisotumab vedotin, which is used for cervical cancer.
MIRASOL: Clinical Implications
Lauren Prescott, MD, MPH:
My takeaway from the confirmatory MIRASOL trial of mirvetuximab soravtansine is that this novel ADC is associated with significant and clinically meaningful improvements in ORR, PFS, and OS vs investigator’s choice of chemotherapy in a very difficult-to-treat population of patients with recurrent, platinum resistant ovarian cancer.
Ritu Salani, MD, MBA:
I think mirvetuximab soravtansine is a good therapy to talk to our patients about. When you show them a response rate 3 times higher than with standard chemotherapy, a better toxicity profile, and encouraging CRs in patients with platinum resistant disease, they see it as a game changer.
I think what I found most exciting about the confirmatory MIRASOL trial is that we had already been using mirvetuximab soravtansine in platinum-resistant or refractory ovarian cancer after 1 to 3 previous therapies based on the accelerated approval supported by the phase III SORAYA trial in patients with 75% or greater expression of FRα.11 It is reassuring to see that this is the best approach for our patients.
Currently, we are sending out our FRα testing, and a few companies are doing it free of charge during a trial period. This is likely going to change when mirvetuximab soravtansine receives full FDA approval. Because many providers are already including FRα testing for primary disease, either via next-generation sequencing or immunohistochemistry testing platform, this will likely become the standard for getting the FRα testing.
FRα testing results will be particularly important if mirvetuximab soravtansine moves earlier in the lines of therapy. Moreover, it would be important to determine if or whether the biomarker changes over time, and whether a repeat biopsy would be needed at progression with frontline therapy. I think that is where translational studies from MIRASOL would be important to answer these questions.
Frontline CT + Bev ± Durva -> Maintenance Bev ± Durva ± Ola in OC With no-BRCA (DUO-O): Study Design
Lauren Prescott, MD, MPH:
Despite improved outcomes with the use of maintenance olaparib with or without bevacizumab in newly diagnosed advanced ovarian cancer, there remains an unmet need for better therapies in subgroups without tumor BRCA mutations.12,13
At ASCO 2023 we saw a planned interim analysis of efficacy and safety for the phase III DUO-O trial evaluating first-line carboplatin/paclitaxel + bevacizumab ± durvalumab followed by maintenance bevacizumab ± durvalumab ± olaparib in newly diagnosed advanced stage III-IV ovarian cancer without tumor BRCA mutation.14 The primary endpoint for DUO-O is PFS per RECIST in the carboplatin/paclitaxel with bevacizumab and durvalumab arm vs carboplatin/paclitaxel with bevacizumab in non-tumor BRCA mutated HRD+ population and ITT patient population. Secondary endpoints included PFS per RECIST by investigator in the carboplatin/paclitaxel with bevacizumab plus durvalumab vs carboplatin/paclitaxel with bevacizumab alone in ITT, OS, and safety. Patients were stratified by timing and outcomes of cytoreductive surgery and geographic region.
DUO-O: Baseline Characteristics
Lauren Prescott, MD, MPH:
The median age of patients in the study was between 58 and 61 years (range: 21-84). Approximately 90% of patients enrolled on the DUO-O study had high grade serous ovarian cancer, 60% had primary upfront surgery, and slightly over one third were HRD+.
DUO-O: PFS for PC + Bev + Durva + Olaparib vs PC + Bev in Non-tBRCAm HRD+ and ITT (Primary Endpoints)
Lauren Prescott, MD, MPH:
Because of the hierarchical testing, PFS was tested first in the HRD+ population and then subsequently in the ITT population. At ASCO 2023, investigators showed the primary endpoint was met with a significantly prolonged median PFS with triplet maintenance vs bevacizumab alone in the non-tumor BRCA mutated (37.3 vs 23.0 months; HR: 0.49; P <.0001) and the ITT (24.2 vs 19.3 months; HR:0.63; P <.0001) populations. Of importance, PFS benefit was consistent across subgroups evaluated. The 12-, 18-, and 24-month PFS rates were all improved for the immunotherapy and PARP inhibitor-containing arm.
Ritu Salani, MD, MBA
Although the results from DUO-O show the study met its primary endpoint of prolonging PFS in patients with non-tumor BRCA mutated HRD+ disease and in the ITT population, when compared to data from other trials such as PAOLA-1 it does not clearly show an advantage.13 If we had a bevacizumab and olaparib control arm in DUO-O, we could better assess the added value of durvalumab immunotherapy as treatment and as maintenance.
DUO-O: PFS for PC + Bev + Durva vs PC + Bev in ITT (Key Secondary Endpoints)
Lauren Prescott, MD, MPH:
Regarding the key secondary endpoint of PFS in the carboplatin/paclitaxel with bevacizumab plus durvalumab arm vs carboplatin/paclitaxel with bevacizumab alone in ITT, although there was a trend towards improvement in median PFS with the addition of durvalumab maintenance therapy, it did not meet statistical significance (P = .13).
DUO-O: Safety Summary
Lauren Prescott, MD, MPH:
With regard to safety outcomes, the addition of durvalumab to bevacizumab did not substantially increase the AEs to what we have previously seen with bevacizumab monotherapy or dual agent olaparib plus durvalumab.13,15
Serious AEs were reported in 39% of patients in the immunotherapy and PARP inhibitor arm compared with 43% in the bevacizumab plus durvalumab arm, and 34% in the single-agent bevacizumab arm.
DUO-O: AEs With Incidence ≥20%
Lauren Prescott, MD, MPH:
The most common AEs in the durvalumab plus olaparib and bevacizumab arm compared with the bevacizumab plus durvalumab arm during the chemotherapy plus maintenance phase included nausea (57% vs 30%), anemia (55% vs 32%), neutropenia (51% vs 45%), and fatigue/asthenia (49% vs 38%).
In the maintenance phase, the most common AEs in the durvalumab plus olaparib and bevacizumab arm compared with the bevacizumab plus durvalumab arm were nausea (52% vs 17%), anemia (41% vs 10%), and fatigue/asthenia (32% vs 20%).
DUO-O: Grade ≥3 AEs With Incidence ≥5%
Lauren Prescott, MD, MPH:
As anticipated with triplet therapy, there was a significant amount of bone marrow toxicity (eg, neutropenia, anemia, and leukopenia), which was likely due to the PARP inhibitor component.
DUO-O: Clinical Implications
Lauren Prescott, MD, MPH:
My take home from the DUO-O trial is that it met its primary endpoint despite lacking a control arm to isolate the effects durvalumab vs the experimental triplet therapy. The authors of the DUO-O study also would say that the reason for the lack of a control arm for durvalumab was that the results of PAOLA 1 were unknown at the time, and when they were known it was too late to go back and change the comparator group in DUO-O. Despite those limitations, this is the first study to open the door to exploring immunotherapy options in the management of ovarian cancer.
Ritu Salani, MD, MBA:
To me, the role of the DUO-O trial results in the clinical setting remain uncertain. I also think the cost of a triplet maintenance regimen will limit its widespread adoption. Moreover, in light of other studies evaluating olaparib and bevacizumab in patients with non-tumor BRCA HRD+ disease it is unclear what the implications for the DUO-O trial are in the clinic. At this point in time, the DUO-O trial is a proof of principle, hypothesis-generating study that has left us wanting in regard to the contribution of durvalumab in the triplet. I think the use of olaparib plus bevacizumab without durvalumab remains a viable option in patients with HRD+ disease.
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