CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: December 13, 2023
Expiration: December 12, 2024
Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in FR𝝰-High PROC (MIRASOL): Study Design
Kathleen Moore, MD, MS:
At ASCO 2023, I presented the results from the global, open-label, randomized phase III MIRASOL trial comparing the antibody‒drug conjugate mirvetuximab soravtansine vs investigator’s choice of chemotherapy in patients with platinum‑resistant recurrent ovarian cancer with high expression of folate receptor α (FRα; N = 453).10 Patients could be enrolled on the MIRASOL study if they had 1-3 previous lines of chemotherapy; they also could have previously received bevacizumab, but it was not required. The primary endpoint was PFS measured by the investigator. Key secondary analytic endpoints were ORR and OS, as well as PROs.
MIRASOL: PFS by Investigator (Primary Endpoint)
Kathleen Moore, MD, MS:
The primary endpoint of PFS by the investigator was met. We showed clinically meaningful and statistically significant PFS improvement for the mirvetuximab soravtansine arm compared with the chemotherapy arm (5.62 vs 3.98 months; P <.0001; HR: 0.65), as well as improvement in response (ORR: 42% vs 16%; complete response: 5% vs 0%). Of importance, at the 3-month mark, approximately 67% of patients in the chemotherapy arm already had discontinued treatment because of progression, and we do not see that in the mirvetuximab soravtansine arm with approximately 33% discontinuing study. In other words, there is an early separation of the curves that is maintained throughout.
MIRASOL: OS
Kathleen Moore, MD, MS:
At this preplanned interim analysis, OS also was significantly improved with mirvetuximab soravtansine compared with chemotherapy (16.46 vs 12.75 months; P = .0056; HR: 0.67), with a 33% reduction in the hazard of death with use of mirvetuximab soravtansine compared with chemotherapy.
MIRASOL: Overall Safety Summary
Kathleen Moore, MD, MS:
From a safety standpoint, we did not see any new AEs from those previously described in previous clinical trials, including the single‑arm phase III study SORAYA.11  Only 9% vs 16% of patients discontinued treatment in the mirvetuximab soravtansine arm because of treatment-emergent AEs vs the chemotherapy arm, respectively.
MIRASOL: Selected Treatment-Emergent AEs
Kathleen Moore, MD, MS:
Of importance, ocular and gastrointestinal AEs of interest were common but of low severity. AE prevention and mitigation strategies are in place for mirvetuximab soravtansine and do work well in these patients. Hematologic AEs were more common with chemotherapy, including grade ≥3 hematologic AEs.
Incorporating Mirvetuximab Soravtansine as a Standard Treatment of Platinum-Resistant Ovarian Cancer
Nicoletta Colombo, MD, PhD:
In the AURELIA study, the addition of bevacizumab to chemotherapy (paclitaxel) improved response and PFS.12 What are your thoughts on the addition of bevacizumab to mirvetuximab soravtansine to improve these outstanding results potentially further? Any thoughts for when best to screen for FRα?
Kathleen Moore, MD, MS:
Thank you for those questions, Dr Colombo. Starting with the easier one first, I would say to test for FRα at the time of diagnosis—or at least at the time of first recurrence. The question regarding adding bevacizumab is a great one. Data from the FORWARD II study evaluating bevacizumab and mirvetuximab soravtansine in 100 patients with either platinum-resistant or platinum-sensitive tumors show ORR of approximately 64% for medium and high expression and approximately 70% in the platinum‑sensitive setting, with a long DoR and no additive toxicity.13 I feel very comfortable offering mirvetuximab soravtansine to my first platinum‑resistant line of therapy with bevacizumab instead of one of the AURELIA chemotherapy partners.12 At this time, we do not yet have randomized data to support this, and I acknowledge that, but I feel very comfortable that I am doing the right thing for my patients with this combination.
Frontline CT + Bev ± Durva → Maintenance Bev ± Durva ± Ola in OC With no-BRCA (DUO-O): Study Design
Nicoletta Colombo, MD, PhD:
Another key study presented at ASCO 2023 for ovarian cancer was the phase III DUO-O trial evaluating frontline carboplatin/paclitaxel chemotherapy plus bevacizumab with or without durvalumab followed by maintenance bevacizumab with or without olaparib and durvalumab or durvalumab placebo (N = 1130).14 The primary endpoint was investigator-assessed PFS per RECIST for carboplatin/paclitaxel chemotherapy plus bevacizumab, durvalumab, and olaparib compared with chemotherapy plus bevacizumab in non‒BRCA-mutated tumors and who had homologous recombination deficiency (HRD), as well as those in the intention-to-treat (ITT) populations.
DUO-O: PFS for PC + Bev + Durva + Olaparib vs PC + Bev in Non-tBRCAm HRD+ and ITT (Primary Endpoints)
Nicoletta Colombo, MD, PhD:
The DUO-O trial met its primary endpoint, with significantly prolonged PFS with the addition of durvalumab plus olaparib to maintenance bevacizumab following first-line carboplatin/paclitaxel plus bevacizumab and durvalumab compared with carboplatin/paclitaxel plus bevacizumab and maintenance bevacizumab in patients with non‒BRCA-mutated tumors.
In patients who were HRD positive, the median PFS was significantly prolonged in the experimental arm at 37.3 vs 23.0 months (HR: 0.49; P <.0001); in the ITT population, the median PFS was 24.2 vs 19.3 months (HR: 0.63; P <.0001). The positive trend was consistent in all clinical subgroups, including surgical strategy used and in patients who were HRD negative.
It is critical to underline that DUO-O is the first phase III clinical trial to meet its primary endpoint in ovarian cancer using an immune oncology agent—in this case durvalumab—in combination with a PARP inhibitor. Although these results are very encouraging, we should remember that DUO-O lacked a control arm to isolate the effects of durvalumab by comparing the experimental triplet therapy with the olaparib/bevacizumab combination that proved successful in PAOLA-1. Despite this limitation, this study opens the door to explore immunotherapy options in ovarian cancer, which had until this time failed to yield a clinical benefit until DUO-O.
Key Data Presented at ASCO 2023 for Cervical Cancer
Kathleen Moore, MD, MS:
I also want to highlight key data presented at ASCO 2023 for cervical cancer, starting with data from the SHAPE trial, and I will walk us through the final OS data presented for the KEYNOTE-826 trial of the addition of pembrolizumab to chemotherapy with or without bevacizumab in advanced cervix cancer.
CCTG CX.5-SHAPE: Radical- vs Simple- Hysterectomy and Pelvic Node Dissection for Low-Risk Early-Stage CC
Kathleen Moore, MD, MS:
I think the SHAPE trial was very exciting—and easily one of the top 10 most important studies presented at ASCO 2023. The CCTG CX.5-SHAPE trial was an international, randomized, phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low‑risk, early‑stage cervical cancer (N = 700).15 Of importance, standard of care for early‑stage cervical cancer has been radical hysterectomy for decades, and the quality of this surgery is incredibly important. We get one opportunity to cure cervical cancer, because if you do not, when these tumors recur, they are incurable.
There are a few important points to make about the SHAPE trial. First, regardless of the assignment of surgical technique, both types of hysterectomy required that a pelvic lymph node dissection be performed; surgeons had the option of doing sentinel lymph node mapping if they chose, but lymph nodes were required. Second, patients who were included in this clinical trial were highly selected to be appropriate for considering this simple hysterectomy approach. Early, small studies really have shown that in these smaller tumors, when looking at the pathology evaluation, there is no spread to the parametria—it is not where they go. Tumors often are found in lymph nodes, but they are not in the parametria, and they are not in the extensive vaginal resection margins, which justified asking the question addressed by the SHAPE trial.
CCTG CX.5-SHAPE: Clinical Outcomes After Median Follow-up of 4.5 Years
Kathleen Moore, MD, MS:
At ASCO 2023, Dr. Marie Plante and colleagues showed that simple hysterectomy was noninferior to radical hysterectomy as assessed by 3-year pelvic recurrence rate (2.52% vs 2.17%, with noninferiority threshold of 95% CI: 4%).
CCTG CX.5-SHAPE: Acute and Late Surgery–Related AEs
Kathleen Moore, MD, MS:
Moreover, simple hysterectomy was associated with fewer urologic surgical complications, better quality of life, and better sexual health measures in patients with early/low-risk cervical cancer.
We saw a significant difference (P <.0001) in urinary retention for acute and late surgery time points both favoring the simple hysterectomy group when compared with the radical hysterectomy group.
CCTG CX.5-SHAPE: QoL and Sexual Health
Kathleen Moore, MD, MS:
We also saw significant differences between 2 groups for sexual vaginal functioning based on the European Organization for Research and Treatment of Cancer Quality of Life questionnaire cervical cancer module and sexual pain based on the female sexual function index pain scale at 3-, 6-, and 12-month assessments, all favoring the simple hysterectomy arm vs radical hysterectomy arm.
Expert Discussions on the CCTG CX.5-SHAPE Trial
Kathleen Moore, MD, MS:
In SHAPE, investigators concluded that following an adequate and rigorous preoperative assessment, simple hysterectomy now can be considered the new standard of care for patients with low-risk, early-stage cervical cancer (with low risk defined as stage IA2-IB1 ≤2 cm, <10 mm depth of stromal, invasion by loop electrosurgical excision procedure/cone, and <50% depth of stromal invasion by preoperative magnetic resonance imaging).
Nicoletta Colombo, MD, PhD:
Dr Moore, the majority of patients in this trial underwent minimally invasive surgery, and there was actually a slight imbalance, with more patients undergoing laparoscopy in the simple hysterectomy group. How do you interpret these results in light of the “Laparoscopic Approach to Cervical Cancer (or LACC)” trial? Does this mean laparoscopic simple hysterectomy is safe for cervical cancer, but laparoscopic radical hysterectomy is not? Again, in this respect, do you believe that the higher proportion of extrapelvic recurrences in the simple hysterectomy group may be related to the laparoscopic approach?
Kathleen Moore, MD, MS:
This is one of the most important questions following the SHAPE trial and in context with the results from LACC trial.16 As a reminder, the LACC trial put an end to minimally invasive surgeries in this setting—primarily laparoscopic radical hysterectomies—and we all converted back to doing open procedures, at least in the United States. The LACC study demonstrated a higher risk of death with the minimally invasive approach, and it was minimally invasive laparoscopic surgery—very little robotic use. In the SHAPE trial, we see more use of robotic interventions, with approximately 25% of patients in each arm who had robotic intervention (40%-50% being laparoscopic). All that we can say from the SHAPE trial is that simple hysterectomy in the setting of cervical cancer was noninferior to radical hysterectomy. I do think this trial gives us a sense that laparoscopic simple hysterectomy is safer than what we saw in LACC with radical hysterectomy, and this remains an ongoing question. The ongoing ROCC trial (NCT04831580) led by Drs Kristin Bixel and Mario Leitao is looking at minimally invasive radical hysterectomy done robotically vs open, and it will include some of these smaller tumors and—we hope—will inform on this question.
Final OS Analysis From KEYNOTE-826: Study Design
Nicoletta Colombo, MD, PhD:
Next, we would like to comment on the abstract reporting the final OS results from KEYNOTE-826 presented by Dr Bradley Monk at ASCO 2023.17 As you may recall, KEYNOTE-826 was a phase III study of pembrolizumab plus chemotherapy with or without bevacizumab vs placebo plus chemotherapy with or without bevacizumab as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer (N = 617). The dual primary endpoints were OS and PFS, per RECIST 1.1 and assessed by investigator review, with each tested sequentially in 3 different populations—PD-L1 combined positive score (CPS) ≥1, PD-L1 CPS ≥10, and all-comers. We published the primary analyses in The New England Journal of Medicine in 2021.18
KEYNOTE-826: Final Analysis of OS
Nicoletta Colombo, MD, PhD:
After a follow-up of 39.1 months, investigators showed that the addition of pembrolizumab to chemotherapy with or without bevacizumab continued to demonstrate clinically significantly prolonged median OS (26.4 vs 16.8 months; HR: 0.63; P <.0001) and median PFS (10.4 vs 8.2 months; HR: 0.61; P <.0001) in the all-comer population. Median OS was improved in PD-L1 subgroups (PD-L1 CPS ≥1: 28.6 vs 16.5 months, HR: 0.60; PD-L1 CPS ≥10: 29.6 vs 17.4 months, HR: 0.58).
KEYNOTE-826: Final Analysis of PFS
Nicoletta Colombo, MD, PhD:
Median PFS also was improved in the PD-L1 subgroups (PD-L1 CPS ≥1: 10.5 vs 8.2 months, HR: 0.58; PD-L1 CPS ≥10: 10.4 vs 8.1 months, HR: 0.52). Of importance, benefit was consistent across subgroups with or without bevacizumab.
KEYNOTE-826: Updated Safety
Nicoletta Colombo, MD, PhD:
Safety outcomes were as expected based on individual agent profiles, with no new safety signals. The most common all cause AEs ≥20% in the pembrolizumab arm and placebo arm were anemia (61.2% and 54.0%), alopecia (56.4% and 57.9%), nausea (39.7% and 43.7%), and diarrhea (37.1% and 30.7%).
The most common immune-mediated AEs more than 2 patients in the pembrolizumab arm and placebo arm were hypothyroidism (19.2% and 10.0%), hyperthyroidism (8.5% and 3.2%), colitis (5.2% and 1.6%), severe skin reactions (4.6% and 0.3%).
The KEYNOTE-826 study has demonstrated that adding immunotherapy to chemotherapy with or without bevacizumab for the treatment of patients with persistent, recurrent, or metastatic cervical cancer is the new standard of care, and later in this module, we will hear from our colleague Dr Ana Oaknin who presented data at ESMO for the phase III BEATcc trial exploring the use of atezolizumab in this setting.
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