Did pembrolizumab improve survival in patients with locally advanced cervical cancer due to poor access to post-protocol care?

We recently published our analysis in the journal Cancer, explaining why we believe an trial testing pembrolizumab in this setting – KEYNOTE-A18 – should not change practice.

The results of the ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial were published recently in The Lancet and presented at a major oncology conference (ESMO 2024).

The authors of this globally-run industry-sponsored trial demonstrated that a higher number of women with locally advanced (but not incurable) cervical cancer would be alive after 3 years of follow-up when treated with 2 years of pembrolizumab (experimental treatment with immunotherapy) in addition to receiving several weeks of chemotherapy and radiation therapy (the standard of care).

In the trial, nearly 13 patients need to be treated with immunotherapy to keep 1 additional patient alive after three years.

The reported findings of the KEYNOTE-A18 have generated enthusiasm and have already led to approval for pembrolizumab for treating women with locally advanced cervical cancer by both the Food and Drug Administration and European Medicines Agency (and will most likely be incorporated in clinical practice guidelines).

In our new Cancer journal paper, we argue that the reported findings should not change clinical practice. We question their reliability and doubt the survival benefit would hold if post-protocol care were optimal. We detail our reasoning here! (Full paper available here.)

Why shouldn't KEYNOTE-A18 change practice?

Findings from an earlier clinical trial (KEYNOTE-826) demonstrated that in women with incurable cervical cancer, the addition of the same immunotherapy drug, pembrolizumab, to the standard of care, prolonged survival. This was presented in September 2021 and incorporated in practice guidelines in October 2021. KEYNOTE-A18 started accrual in June 2020.

General oncology principles…

A basic principle in cancer treatment: moving a treatment to an earlier phase of disease, based on disease biology and patient eligibility/physical condition, often results in more patients being exposed to the treatment for a longer time.

When a treatment improves survival in an incurable phase (like in KEYNOTE-826), it will often subsequently be tested in a clinical trial in patients who will be treated with curative intent – aiming to increase the fraction of patients cured – before a patient becomes incurable. This is the adjuvant setting, like in KEYNOTE-A18.

In the adjuvant setting, by definition, an (often large) number of patients will be exposed to the experimental treatment who would have been cured anyway (but nonetheless exposed to the toxicity of the experimental treatment). A number of patients will be exposed to the experimental treatment but die of their cancer anyway. In a positive clinical trial, a (usually small) fraction of patients will be cured (or live longer) due to the experimental treatment.

… applied to pembrolizumab in locally advanced cervical cancer

• If at the time of initiation, the KEYNOTE-826 results were not yet known, the KEYNOTE-A18 should not have been initiated yet.

• If the results were known (trials were run by the same sponsors and overlapping authors), cross-over to pembrolizumab should have been guaranteed per protocol for patients in the control arm of the trial.

• When the KEYNOTE-826 results became available most patients participating in the KEYNOTE-A18 would not yet have recurred and as such, an amendment to the KEYNOTE-A18 protocol should have been made that guaranteed optimal post-recurrence care with cross-over per protocol (pembrolizumab next to chemotherapy).

When a patient's disease recurs or progresses, the study treatment (whether experimental or control) will be discontinued. The treatment that patients then receive after the study treatment is called the post-protocol treatment.

The KEYNOTE-A18 should have addressed the key question at hand: “Do we improve survival by exposing all patients in the curative setting to pembrolizumab, or would survival be the same if we limit pembrolizumab exposure to only those patients that, in time, become incurable”.

However, this question would only be answered if patients randomised to placebo would have all received optimal post-protocol treatment, including pembrolizumab, in case they became incurable.

Sadly, in KEYNOTE-A18, when control-group patients recurred, access to pembrolizumab was not guaranteed. At the time of the reported analysis, only 51 of 193 (26%) patients that became incurable in the control group received immunotherapy as a post-protocol treatment (41 of 51 were treated with pembrolizumab). Also, no data regarding post-protocol treatment with chemotherapy and bevacizumab were made available. Thus, most patients in the control arm (treated with chemotherapy and radiation therapy) did not receive immunotherapy when their cancer relapsed or progressed, whereas by definition, every patient in the experimental arm initially received immunotherapy. The results are thus based on exposing everyone in the experimental arm to immunotherapy, as compared to only a quarter of patients in the control arm at the later stage.

The results are therefore, alas, non-informative. The modest survival benefit may well be only the result of withholding the standard of care in the control arm patients. Those benefits could have evaporated if the control arm patients had proper access to pembrolizumab upon recurrence.

A difference between White and non-White patients?

Interestingly, the investigators did an analysis per protocol to compare White to non-White patients.

It seemed that the reported OS benefit was limited to non-White patients (51% of all patients). It did not work at all in White patients.

This finding supports our hypothesis. It is well known that access to any treatment (let alone costly immunotherapy) is higher in White patients. It may well be that White patients with cancer progression in the control arm of the KEYNOTE-A18 had better access to any post-protocol treatment as compared to non-White patients. This suggests that indeed there is no advantage to administering pembrolizumab early in the treatment landscape of women with cervical cancer.

Next to the doubt of the validity of the reported findings, a calculation shows that it costs nearly 3 million dollars to prevent one death after three years ($2.729.375 based on the methodology described here). The treatment duration – 2 years – also raises concerns.

Concluding words

The main reason for suboptimal post-protocol care is that trials are conducted globally, including in countries with limited or no access to optimal treatment upon recurrence. This was described in many trials leading to marketing authorisations. Taken together and based on the above, we feel that pembrolizumab should not be adopted in clinical practice guidelines for treating patients with locally advanced cervical cancer based on the data as reported. Read our full analysis here (also available here).