CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: August 17, 2022
Expiration: August 16, 2023
Angeles Alvarez Secord, MD, MHSc:
As we move into discussing cervical cancer, I want to start with some historical context. The phase III Gynecologic Oncology Group 240 (GOG 240) trial, which evaluated chemotherapy with or without bevacizumab in patients with advanced or recurrent cervical cancer, was a pivotal trial that changed the standard of care. With the incorporation of bevacizumab, median PFS increased from 5.9 to 8.2 months (hazard ratio: 0.67; 95% CI: 0.54-0.82; P = .002) and median OS in the updated analysis increased from 13.3 months to 16.8 months (hazard ratio: 0.77; 95% CI: 0.62-0.95; P = .007).40,41 ORR in the bevacizumab‑containing arms were 49% to 51%, with CR rates of 12% to 16%. These results established chemotherapy plus bevacizumab as standard of care in cervical cancer.
Angeles Alvarez Secord, MD, MHSc:
Pembrolizumab and chemotherapy with or without bevacizumab also is approved as first-line treatment for patients with PD‑L1–positive recurrent or metastatic cervical cancer, based on data from the phase III KEYNOTE-826 trial showing improvement in both OS and PFS.42 However, recurrent cervical cancer still is associated with poor outcomes, and there is a clear unmet need for more effective treatment options.
The phase II ENGOT Cx8/GOG 3024/innovaTV 205 trial is assessing the antibody–drug conjugate tisotumab vedotin in combination with pembrolizumab, carboplatin, or bevacizumab in patients with recurrent or metastatic cervical cancer. Tisotumab vedotin has received FDA approval in this population for patients with disease progression on or after chemotherapy, based on an ORR of 24% and a DoR of 8.3 months.43,44
At the 2022 ASCO Annual Meeting, Lorusso and colleagues45 presented interim phase II safety and efficacy results of tisotumab vedotin combinations as first- or later-line therapies.
Angeles Alvarez Secord, MD, MHSc:
The innovaTV 205 study included a phase I dose escalation of tisotumab vedotin followed by phase II dose expansion in 3 combination cohorts. Cohort 1 included patients with no prior systemic therapy who received tisotumab vedotin with pembrolizumab (n = 33). Patients in cohort 2 had disease progression on 1 or 2 prior therapies and received tisotumab vedotin with pembrolizumab (n = 35). Lastly, cohort 3 enrolled patients with no prior therapy who received tisotumab vedotin with carboplatin (n = 33).
The phase II primary endpoint are ORR per RECIST criteria, and secondary outcomes are AEs and laboratory parameters, DoR, time to response, PFS, and OS.
Angeles Alvarez Secord, MD, MHSc:
This trial enrolled younger patients, with a median age of 47-51 years. Most women were non‑Hispanic White and, the majority, had an excellent performance status of 0; 54% to 73% across the 3 cohorts had squamous lesions. In the cohorts receiving pembrolizumab, PD‑L1 was ≥1 in 96.6% of patients in the frontline setting and in 81.5% of patients in the second and third‑line setting. Most patients had received previous radiation therapy and inclusion of chemotherapy. Approximately 54.3% of patients in the second-line and third‑line setting had previously received bevacizumab.
Angeles Alvarez Secord, MD, MHSc:
In terms of response, reduction in target lesion was observed across treatment arms with very encouraging waterfall plots showing that 74% to 85% achieved a reduction in their tumor burden.
Angeles Alvarez Secord, MD, MHSc:
In patients receiving first‑line tisotumab vedotin plus pembrolizumab, the confirmed ORR was 40.6% and the median PFS was 5.3 months. With a median follow-up of 18.8 months, the median OS and median DoR had not yet been reached, and some patients had durable, ongoing responses beyond 15 months.
Angeles Alvarez Secord, MD, MHSc:
Among patients receiving second-line and third‑line tisotumab vedotin plus pembrolizumab, the ORR was 38.2% and median DoR was 14.0 months (range: 2.8 months to not reached). Median PFS was 5.6 months and median OS was 15.3 months. These findings are in line with the GOG 240 data, which included bevacizumab.41
Angeles Alvarez Secord, MD, MHSc:
In the third cohort, patients receiving first-line tisotumab vedotin plus carboplatin, the ORR was 54.5%, median PFS was 6.9 months, and the median OS had not yet been reached (range: 0.8-22.1+ months). Median DoR was 8.6 months (range: 4.2-11.5), but some patients had responses ongoing beyond 12 months.
It will be exciting to watch as the data from these cohorts mature. We can hope to see other treatment options moving into the frontline setting to build on the chemotherapy/bevacizumab standard or even moving into a nonchemotherapy option.
Angeles Alvarez Secord, MD, MHSc:
Observed AEs were consistent with the expected toxicity profiles of each agent. Several AEs were present in over 25% of the patients, but grade ≥3 events were relatively rare.
In the first-line tisotumab vedotin plus pembrolizumab cohort, the most common grade 1/2 AEs included alopecia (58%), epistaxis (48%), conjunctivitis (42%), dry eye (39%), and anemia (18%), and the most common grade ≥3 AEs was anemia (12%) with other grade ≥3 AEs observed at a frequency of 3% or lower.
In the second-line to third-line cohort of tisotumab vedotin plus pembrolizumab, the most common grade 1/2 AEs included diarrhea (49%), epistaxis (37%), anemia (26%), conjunctivitis and dry eye (26% each), and the most common grade ≥3 AEs were anemia (29%), fatigue (9%), decrease appetite (9%), asthenia (9%), urinary tract infection (6%), hypokalemia (6%), and hypomagnesemia (6%).
In the first-line cohort of tisotumab vedotin plus carboplatin the most common grade 1/2 AEs were nausea (64%), fatigue (49%), and alopecia (55%), dry eye (42%), epistaxis (39%), and conjunctivitis (33%), and the most common grade ≥3 AEs included anemia (39%), nausea and diarrhea (15% each), and neutropenia (12%).
There was 1 grade 5 event reported in the first-line pembrolizumab cohort that was considered treatment-related due to disseminated intravascular coagulation.
Angeles Alvarez Secord, MD, MHSc:
There are a few AEs of special interest with tisotumab vedotin, and these occurred at similar rates across the 3 cohorts. Grade ≥3 ocular events were present in 51% to 58% of patients of each cohort, but it is not clear whether these were clinically significant. There are prophylactic eye care regimens in place to help mitigate ocular toxicity with tisotumab vedotin, and patients need to be followed closely by either an ophthalmologist or optometrist.
Bleeding abnormalities did occur, with grade ≥3 bleeding events in 52% to 61% of patients in each cohort. However, catastrophic bleeding abnormalities were very rare.
Peripheral neuropathy also is a common AE to be expected with tisotumab vedotin, and grade ≥3 AEs were seen in 37% to 49% of patients across the cohorts.
Angeles Alvarez Secord, MD, MHSc:
In the innovaTV 205 clinical trial, tisotumab vedotin in combination with pembrolizumab or carboplatin chemotherapy demonstrated promising and durable antitumor activity with a tolerable safety profile in patients with recurrent or metastatic cervical cancer.
Investigators concluded that these data suggest potential for tisotumab vedotin to be included in a combination regimen to improve clinical outcomes in first-line recurrent or metastatic cervical cancer.
I will be very interested to see how these data are incorporated into new clinical trial designs. For example, a new cohort will be added to this ongoing phase I/II study to investigate the combination of tisotumab vedotin, carboplatin and pembrolizumab with or without bevacizumab as a first‑line treatment in patients with recurrent or metastatic disease (NCT03786081).
Angeles Alvarez Secord, MD, MHSc:
As I mentioned previously, the phase III KEYNOTE‑826 trial of pembrolizumab in combination with chemotherapy with or without bevacizumab led to the FDA approval of this regimen in patients with persistent, recurrent metastatic cervical cancer with a PD-L1 CPS score of ≥1. The primary analysis showed clinically meaningful results for PFS and OS with the addition of pembrolizumab vs chemotherapy with or without bevacizumab alone.42Colombo 2021 The analysis presented at the ASCO 2022 Annual Meeting further discusses efficacy outcomes in several key patient subgroups within that trial.46
Angeles Alvarez Secord, MD, MHSc:
KEYNOTE-826 randomized 617 patients 1:1 to receive pembrolizumab 200 mg IV with chemotherapy, with or without bevacizumab 15 mg/kg IV, every 3 weeks, or to receive placebo and chemotherapy with or without bevacizumab.
The dual primary endpoints were investigator-assessed OS and PFS. Secondary endpoints were ORR, DoR, 12‑month PFS, and safety. Exploratory endpoints included patient-reported quality of life per the European Quality of Life 5-dimension, 5-level visual analogue scale.
Angeles Alvarez Secord, MD, MHSc:
The median ages were similar between treatment arms, 51 years in the pembrolizumab‑containing arm and 50 years in the placebo arm. Patients had an excellent performance status, with more than 40% with a performance status of 1. Most patients had squamous cell cancers and a PD‑L1 CPS score ≥1; only 11% of patients in each arm had a CPS score <1.
Also, most patients had previously received treatment with chemoradiation or radiation therapy with or without surgery. Patients had a wide cross‑section of disease stages, but approximately 30% of patients in each arm initially presented with stage IVB disease, and most patients had either persistent or recurrent disease (58% to 65%).
Bevacizumab use during the study was 63.6% in patients receiving pembrolizumab and 62.5% in patients receiving placebo.
Angeles Alvarez Secord, MD, MHSc:
As previously discussed, the trial met its primary endpoint with significantly longer median PFS and OS in the pembrolizumab arm in the full patient population. In an exploratory analysis, both PFS and OS were numerically higher in the pembrolizumab arm across multiple key patient subgroups as well.
In patients with squamous cancers, median PFS was 10.4 months with pembrolizumab compared with 6.9 months with placebo (hazard ratio: 0.63), while median OS was 23.5 months with pembrolizumab compared with 14.2 months with placebo (hazard ratio: 0.61). These results are very exciting to see, and I am also very interested in the outcomes in patients with nonsquamous cancers. Clinically, adenocarcinoma patients tend to have a worse prognosis. In this group, median PFS was 11.6 months with pembrolizumab compared with 8.4 months with placebo (hazard ratio: 0.66). An exciting result is that the median OS had not yet been reached in pembrolizumab arm group compared with 21.3 months in the placebo arm (hazard ratio: 0.76).
In the clinic, there is always the question of whether to use cisplatin or carboplatin. Here, patients treated with either type of chemotherapy showed a benefit in combination with pembrolizumab (hazard ratio with cisplatin and carboplatin: 0.47 and 0.69, respectively), although the magnitude of benefit might be a bit larger with cisplatin. My treatment choice is to utilize carboplatin in patients who have been previously treated with a cisplatin‑containing regimen. In chemotherapy naive patients, I typically use cisplatin containing regimens.
Another important consideration is whether to use bevacizumab. In this subgroup analysis, the patients who were treated with bevacizumab had a longer median PFS of 15.2 months with pembrolizumab compared with 10.2 months with placebo (hazard ratio: 0.61); and longer median OS (not reached in the pembrolizumab arm compared with 24.7 months in the placebo arm; hazard ratio: 0.63). Patients who did not receive concomitant bevacizumab had shorter survival and a no benefit with pembrolizumab. Median PFS was 6.3 months with pembrolizumab compared with 6.2 months with placebo (hazard ratio: 0.74), and median OS was 16.8 months with pembrolizumab vs 12.6 months with placebo (hazard ratio: 0.74). In this study, the use of bevacizumab was based on investigator decision and patient preference and could be biased toward patients more likely to do well on it, so it is harder to attribute effects to the bevacizumab. Certainly, however, these exploratory findings indicate a benefit of bevacizumab in this setting.
Finally, the investigators examined outcomes based on whether patients had received previous radiation therapy. From a clinical standpoint, we have sometimes seen decreased response to chemotherapy agents in the irradiated field that was thought to be due to a decreased delivery of chemotherapy to that site, perhaps because of disruption of vasculature from radiation. The same mechanism could affect the efficacy of pembrolizumab. However, we see similar PFS outcomes with pembrolizumab with or without prior radiation, at 10.3 and 10.4 months respectively, and both are longer than with placebo. Among patients with prior radiation therapy, median OS was 21.3 months with pembrolizumab compared with 12.6 months with placebo; for those who had not received prior radiation, median OS was not reached with pembrolizumab compared with 19.4 months with placebo (hazard ratio: 0.71).
Angeles Alvarez Secord, MD, MHSc:
The same was true among patients who had a PD-L1 CPS score ≥1. Recall, however, that this agent is only approved for patients with a PD‑L1 CPS score ≥1, and the trial enrolled a relatively small number of patients with PD‑L1 <1, probably too small a group to demonstrate any relative benefit. That patient group remains in need of novel therapies.
Angeles Alvarez Secord, MD, MHSc:
ORRs show similar patterns as survival outcomes across the key patient subgroups. Moreover, we can see a benefit with pembrolizumab compared with placebo in patient subgroups within all-comer populations and those with PD-L1 CPS score ≥1.
Angeles Alvarez Secord, MD, MHSc:
In conclusion, pembrolizumab and chemotherapy, with or without bevacizumab, prolonged PFS and OS compared with placebo in patients with recurrent or metastatic cervical cancer.
The investigators concluded that these data further support the use of pembrolizumab with chemotherapy, with or without bevacizumab, as a new standard of care for patients with persistent, recurrent, or metastatic disease.
Angeles Alvarez Secord, MD, MHSc:
The takeaway of this exploratory analysis from KEYNOTE-826 is that several patient subgroups in the all-comer patient population showed a PFS and OS benefit with the addition of pembrolizumab.
I have routinely incorporated the use of pembrolizumab and, depending on patient factors, bevacizumab with chemotherapy in the treatment of my patients, and I agree with the author’s conclusion. Although this subgroup analysis is exploratory, I think it provides interesting information related to disease histology and prior treatment that may be clinically useful.
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