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Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2021 ASCO Annual Meeting
  • CME

Joyce O'Shaughnessy, MD
Angeles Alvarez Secord, MD, MHSc
Released: August 12, 2021

Endometrial Cancers

TOTEM: Intensive vs Minimalist Follow-up in Patients Treated for Endometrial Cancer

Angeles Alvarez Secord, MD:
At the ASCO 2021 annual meeting, Zola and colleagues reported results from the multicenter TOTEM study—a very important and clinically relevant study of surveillance in patients with endometrial cancer. Now that patients are more connected around the world via chatrooms and social media, they often hear about patients who are being highly surveilled with CT scans or even PET scans. Every week, patients ask me about how they should be followed for their endometrial cancer. TOTEM is an incredibly relevant study because it provides us with information on how to counsel our patients.

The TOTEM study enrolled 1866 patients who were older than 18 years of age and who had histologically confirmed diagnosis of endometrial cancer, of any stage, with no residual macroscopic tumor after surgery and no previous or concomitant second neoplasm or hereditary syndrome.44 All patients enrolled were stratified by risk level. The high‑risk group comprised patients with stage IA grade 3 disease or greater than or equal to stage IB disease. The low‑risk group included patients with stage IA grade 1/2 disease. 

Patients were randomized to receive 5 years of either intensive follow-up or minimalist follow-up. High‑risk patients in the intensive follow-up group received clinical examination and CA-125 tests every 4 months for 3 years and then every 6 months. They also underwent abdominal and transvaginal ultrasound at 4, 8, 16, 20, 28, 32, 42, and 54 months, as well as a yearly CT scan and Pap smear. Low‑risk patients in the intensive follow-up group underwent clinical examination every 4 months for 2 years and then every 6 months, and they had yearly pap smears and yearly CT scans for 2 years. High‑risk patients in the minimalist follow-up group received clinical examination every 4 months for 2 years and then every 6 months, and a yearly CT scan for 2 years. Low‑risk patients in the minimalist follow-up group received only clinical examination every 6 months. The primary endpoint of this study was OS. Key secondary endpoints were RFS, health‑related quality of life, compliance to follow-up, and cost. I think it is incredibly important that they added cost as a key endpoint for this study.

TOTEM: Baseline Characteristics

Angeles Alvarez Secord, MD:
In terms of baseline characteristics, the treatment arms were well balanced. The median age was 64 years in the intensive follow-up arm and 63 years in the minimalist follow-up arm. Most patients in both arms had endometrioid cancer stage IA, grade 1/2 disease (59.0% and 58.9%, respectively). Consequently, most patients fell into the low‑risk category. We saw that 50.4% and 49.5% in the intensive follow-up group and minimalist follow-up group, respectively, had laparoscopic surgery, and 66.7% and 66.3% of patients, respectively, had surgery alone as their treatment.

TOTEM: OS

Angeles Alvarez Secord, MD:
In the overall population, the OS curves for intensive and minimalist follow-up are essentially superimposed. There is no difference in OS whether a patient is undergoing intensive or minimalistic surveillance (HR: 1.12; 95% CI: 0.85-1.48; P = .424). We see similar superimposable OS curves when data are further stratified into the low‑risk (HR: 1.48; 95% CI: 0.92-2.37; P = .104) and high‑risk groups (HR: 0.96; 95% CI: 0.68-1.36; P = .814). Clearly, there does not appear to be any overall survival benefit with intensive compared with minimalist follow-up management. 

TOTEM: RFS by Risk

Angeles Alvarez Secord, MD:
We also see very similar outcomes for RFS. In both risk groups, the RFS curves are almost superimposable when comparing intensive with minimalist follow-up management (low-risk [HR: 1.45; 95% CI: 0.95-2.22; P = .085] and high-risk [HR: 1.00; 95% CI: 0.72-1.39; P = .997]).

TOTEM: Endometrial Cancer Recurrences

Angeles Alvarez Secord, MD:
The relapse rate was 12.3% in the total patient population. A closer look at the patterns of recurrence shows that many patients—50.4% in the intensive follow-up group and 46.7% in the minimalist follow-up group—had distant recurrent disease, which obviously is difficult to identify with physical or pelvic examination. And as we already discussed, the type of follow-up did not change survival or RFS outcomes.

TOTEM: Quality of Life (SF12 PCS and MCS)

Angeles Alvarez Secord, MD:
Patient quality of life was not impaired with either intensive or minimalistic follow-up based on the physical component summary scale (low-risk [mean difference: 0.51; 95% CI: -0.47 to 1.48; P = .308] and high-risk [mean difference: 0.33; 95% CI: -1.05 to 1.70; P = .641]) or mental component summary scale (low-risk [mean difference: 0.55; 95% CI: -0.58 to 1.67; P = .341] and high-risk [mean difference: -0.23; 95% CI: -1.74 to 1.28; P = .765]). Of importance, this also included psychological quality of life. I often worry that incorporating more intensive surveillance could actually add more anxiety for patients. But another consideration is that minimal surveillance could increase anxiety about not being watched as closely. But neither one appeared to affect patients’ psychological quality of life in this study, which I believe is an important finding from this study.

TOTEM: Clinical Implications

Angeles Alvarez Secord, MD:
In terms of how to translate this information to clinical practice, I think the results are clear that an intensive surveillance approach is not needed for all women with endometrial cancer and that our current surveillance options are not sufficient to identify patients with recurrent disease. However, there are some caveats. For the highest‑risk patients, could there be a potential benefit to different types of surveillance in the future? Targeted imaging approaches or more sophisticated modes of testing would warrant future evaluation. 

Another important consideration is that we do not yet have suitable treatments for those women whose disease does recur. It has been incredibly difficult in endometrial cancer to develop novel therapies and we’re just starting to see immunotherapies showing strong clinical benefit in some patients. In the future, if we have a therapy that will really translate to higher disease control for patients, it might be worthwhile to implement a strategy to identify those 12% of patients most likely to have recurrence. Likely, this will be relegated to the higher‑risk population. Presently, what can I tell my patients? For those with low‑risk disease, there certainly is no need to do more intensive surveillance, but I would certainly discuss symptoms that are suggestive of recurrence. In patients with high‑risk disease, I typically talk about what to watch for in terms of symptoms of recurrence, and I perform physical examinations. I do CT scans if indicated based on previous imaging results, and I follow the Society of Gynecologic Oncology and Choosing Wisely guidelines.45

Phase II of Niraparib With or Without Dostarlimab in Recurrent Endometrial Cancer: Study Design

Angeles Alvarez Secord, MD:
The next study I would like to discuss was a nonrandomized phase II study of niraparib with or without dostarlimab in 47 women with recurrent serous or endometrioid endometrial cancer.46 Patients were assigned to one of 2 cohorts: Patients in Cohort 1 (n = 25) received niraparib 300 mg orally daily (or 200 mg if <77 kg or baseline platelets <150,000/µL); patients in Cohort 2 (n = 22) received niraparib 300 mg orally daily (or 200 mg if <77 kg or baseline platelets <150,000/µL) plus dostarlimab 500 mg intravenously every 3 weeks for 4 weeks, then 1000 mg every 6 weeks. There was no limit on the previous lines of systemic therapy, but no previous immunotherapy was allowed for patients in the niraparib plus dostarlimab cohort.

This study was not a comparative study, and each arm was evaluated separately. The primary endpoint was clinical benefit rate (CBR), which included CR, PR, or stable disease at or beyond 16 weeks. Secondary endpoints included ORR rate and safety, as well as biomarkers of response as assessed in archival tissue. However, evaluating biomarkers is very hard in such a small study, so even a negative finding would not rule out the potential significance of biomarkers in this population.

Phase II of Niraparib With or Without Dostarlimab in Recurrent Endometrial Cancer: Baseline Characteristics

Angeles Alvarez Secord, MD:
Most patients in this study were over the age of 60 and had high‑risk serous histology; 72% and 68% in the niraparib cohort and the niraparib plus dostarlimab cohort, respectively, had platinum‑resistant disease. The number of previous therapies was quite high, with a median of 2 (range: 1-4) and 2 (range: 1-6) in the niraparib cohort and the niraparib plus dostarlimab cohort, respectively. Of note, 4 patients in the niraparib and dostarlimab cohort had biomarkers of interest: 3 (14%) had mismatch repair-deficient tumors and 1 (5%) had a POLE mutation.

Phase II of Niraparib With or Without Dostarlimab in Recurrent Endometrial Cancer: Efficacy

Angeles Alvarez Secord, MD:
The spider plots presented for the study show interesting efficacy in each cohort. With the niraparib monotherapy cohort, only 1 of 23 evaluable patients had an objective response, for an ORR of 4% and a CBR of 20%, showing that single‑agent niraparib does not have high clinical activity in this heavily pretreated, unselected patient population. With the niraparib and dostarlimab combination, 3 patients experienced an objective response for an ORR of 14% and a CBR of 31.8%. Of note, the 3 responders in the combination arm had biomarkers of interest (n = 1, PTEN loss; n = 1, with dMMR status; and n = 1, POLE tumor mutation burden–high). Two patients treated with the combination also had prolonged duration of clinical benefit. I believe this trial will continue to yield interesting information, and I eagerly await future updates.

Phase II of Niraparib With or Without Dostarlimab in Recurrent Endometrial Cancer: Safety

Angeles Alvarez Secord, MD:
There were no new safety signals, and the safety profiles were consistent with what is expected for these agents. The most common grade 3 or higher AEs were anemia (24% and 27%), fatigue (16% and not reported [NR]), thrombocytopenia (16% and 9%), and neutropenia (NR and 16%) in the niraparib monotherapy cohort and the niraparib plus dostarlimab cohort, respectively. Of interest, the addition of dostarlimab to niraparib did not appear to increase toxicity over what you would expect with the niraparib monotherapy cohort. The discontinuation rate due to an AE was 14% in the niraparib monotherapy cohort and 9% in the niraparib and dostarlimab combination cohort.

Phase II of Niraparib With or Without Dostarlimab in Recurrent Endometrial Cancer: Clinical Implications

Angeles Alvarez Secord, MD:
Although small, this study brings forward promising information regarding antitumor activity as well as a manageable safety profile for the combination of a PARP inhibitor and anti–PD-L1 immunotherapy. The combination of niraparib and dostarlimab is being evaluated as an arm in the large, randomized, phase III RUBY/ENGOT-EN6/GOG 3031 trial (NCT03981796) of dostarlimab in combination with chemotherapy in women with advanced and recurrent endometrial cancer, and at my site we are enrolling patients on that study.

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