Improving Outcomes for Patients With Anal Cancer By Raising Awareness

Sheela Rao, MBBS, MD, FRCP

Advances in the treatment of anal cancer including refined chemoradiotherapy regimens and the introduction of immunotherapy-based approaches have further improved outcomes, however a lack of focus on early detection has contributed to rising incidence rates, underscoring the importance of disease awareness among patients and health care providers, according to Sheela Rao, MBBS, MD, FRCP.

“[Bringing awareness to anal cancer] is important because to a certain extent, unlike other cancers, there is often a stigma associated with the diagnosis,” Rao said in an interview with OncLive® for Anal Cancer Awareness Day. “That can mean patients aren’t presenting early enough and that is a real tragedy. This is a curable cancer, as long as we detect it early, and most patients will not need surgery. Early detection equals eradication, so [we are] trying to educate patients, caregivers, and health care professionals to look for this disease.”

In terms of recent progress with immunotherapies in the space, during the 2024 ESMO Congress Rao presented data from the phase 3 POD1UM-303/InterAACT 2study (NCT04472429).1 The trial compared retifanlimab-dlwr (Zynyz) with placebo, both in combination with standard-of-care carboplatin and paclitaxel, in patients with locally recurrent or metastatic squamous cell carcinoma of the anal canal.

Data from the study showed that patients who received retifanlimab (n = 154) achieved a median progression-free survival (PFS) by blinded independent central review of 9.3 months (95% CI, 7.5-11.3) vs 7.4 months (95% CI, 7.1-7.7) in the placebo arm (n = 154; HR, 0.63; 95% CI, 0.47-0.84; P = .0006). Additionally, the median overall survival (OS) adjusted for crossover was 29.2 months (95% CI, 24.2-not estimable) vs 19.1 months (95% CI, 13.4-27.9), respectively (HR, 0.63; 95% CI, 0.44-0.90; P = .0055). The overall response rates (ORRs) were 56% (95% CI, 48%-64%) vs 44% (95% CI, 36%-52%), respectively, and the median durations of response (DOR) was 14.0 months (95% CI, 8.6-22.2) vs 7.2 months (95% CI, 5.6-9.3), respectively.

In the interview, Rao discussed the evolution of the anal cancer therapeutic landscape and biomarker development progress, and also looked ahead to the future of the space. Rao is a consultant medical oncologist specializing in gastrointestinal cancers and cancers of unknown primary within the Gastrointestinal Unit at the Royal Marsden Hospital in London, England.

OncLive: What is the present treatment landscape of anal cancer and how has it evolved over the years?

Rao: Anal cancer is a rare cancer, but the instance has been increasing rapidly over the past few years. The mainstay of treatment was formulated based on many trials [and] we split [treatment approaches] into [those for] localized and advanced disease.

In the localized setting, going back to [when] chemoradiation was studied, they identified that surgery wasn’t [usually] necessary in this disease and chemoradiation was able to cure most patients. That was based on a number of trials [including] ACT I, [the phase 3] ACT II study, and the [phase 2] UNICANCER ACCORD 16 study. [Data from select trials] showed that 5-fluorouracil [5-FU] and mitomycin combined with radiotherapy delivered as a long course of treatment was able to eradicate the disease for most patients, leaving just a few with residual or recurrent disease that might need surgery.

One of the next big questions is, now that these patients are surviving, what can we do to improve outcomes? That’s been the subject of more recent research. The other big question is how to avoid a stoma for these patients. A lot of research [has been] about trying to avoid stomas early on, or permanent stomas, for these patients.

In the advanced setting, [progress] has been a bit slower. In 2020, with the [phase 2] InterAACT study [NCT02051868] data we established a chemotherapy regimen in the advanced setting with carboplatin and paclitaxel.We showed that compared with cisplatin and 5-FU, which is the other commonly used regimen, [carboplatin and paclitaxel] was better tolerated and produced similar ORRs, [with] an improvement in OS. That became the recommended treatment regimen, both in the ESMO and NCCN guidelines, for patients with advanced disease. There has been [recent] research trying to improve on that chemotherapy backbone. We [are trying to] improve outcomes for these patients by adding different drugs or modulating chemotherapy.

What has been the impact of the introduction of immunotherapy agents into the paradigm?

[Approximately] 90% of these cancers are linked to human papillomavirus [HPV]. That’s important in terms of research because the virus is integrating into [cells] early on, leading to depleted T cells. [This is] a very immunogenic environment and the question has been [what] can immunotherapy add to this?

Immune checkpoint inhibitors—including retifanlimab, pembrolizumab [Keytruda], and nivolumab [Opdivo]—were initially studied [as monotherapy in] patients who [experienced disease progression] with chemotherapy. The phase 2 NCI9673 study [NCT02314169] of nivolumab [included] 37 patients, the phase 2 KEYNOTE-158 study [NCT02628067] of pembrolizumabincluded 112 patients, [and] the phase 2 POD1UM-202 trial [NCT03597295] of retifanlimab included 94 patients. ORRs [in these studies] were not huge in that setting, ranging from [11% to 24%]. Initially, [this was] not quite the signal we expected, [but there was] some activity.

[However], drilling down into those studies, there were patients who had higher response rates than that with durable responses. But it wasn’t clear from those studies exactly which patients responded, but there was definitely a signal that [immunotherapy] worked. [Data from] those studies led to [the examination of] combining immunotherapy upfront with chemotherapy. To date, we’ve had 2 studies look at that.

The phase 2 SCARCE C17-02 PRODIGE 60 trial [NCT03519295] examined triplet chemotherapy with docetaxel, cisplatin, and fluorouracil, and added atezolizumab [Tecentriq].In the intention-to-treat population, this study was negative; they did not see a benefit in terms of PFS when adding immunotherapy to the chemotherapy. [However], there were some patients who benefited. For example, patients with a higher PD-L1 combined positive score [CPS] benefited, but for the whole population it was a negative study.

The other study, which I recently reported on, is POD1UM-303/InterAACT 2, and interestingly this study was positive. We saw an increase in ORR, a [near] doubling of DOR, and an improvement in PFS with a HR of 0.63. We also saw an improvement in OS; these are immature data, with confidence intervals [that are] not yet reached, but they’re showing a positive signal across all efficacy end points. [The regimen] was well tolerated, we were able to deliver the treatment, and there were not any unexpected [safety] signals.

We’re awaiting [data from the] phase 3 EA2176 study [NCT04444921]which is examining adding nivolumab to carboplatin and paclitaxel. Those results are awaited, but certainly we have a positive study [in POD1UM-303/InterAACT 2], which has been effectively practice changing.

Are there any effective biomarkers that can be used for treatment selection?

The biomarker question is a good one, and it’s one that we need more work on. [Due to] the [presence of] HPV, one can measure HPV circulating tumor DNA [HPV ctDNA], and there have been studies suggesting that could be a biomarker because it is raised at the beginning of treatment, even in the locoregional setting. In those studies, they’ve shown that patients who clear HPV ctDNA don’t relapse. [Comparatively], patients who haven’t fully cleared, or for whom that marker goes up for, look as though they may relapse. This needs to be studied properly in larger clinical trials to be validated, but it does look as though it could be a useful end point.

The same applies in the advanced setting and we’re looking to confirm this in POD1UM-303/InterAACT 2. It has also been shown that a drop in HPV ctDNA can be a marker of response. It looks promising, but this is something that we need to confirm.

Tumor mutational burden is another biomarker that’s been examined in a lot of other cancers, [however] in anal cancer, it does not play out [as a biomarker]. These patients don’t have a particularly high tumor mutational burden to start with, and it doesn’t change [significantly]. So that’s not a good biomarker in this setting.

Another [biomarker of interest] is PD-L1 CPS with immunotherapy. More work is being done in POD1UM-303/InterAACT 2 to understand if it correlates [with efficacy]. In SCARCE C17-02 PRODIGE 60 it did correlate [with activity], but whether it has any [value] in the localized setting, we don’t know yet. It may be that as we enrich for [PD-L1] CPS it may be a biomarker correlated with the efficacy of immunotherapy, but that’s something we need to confirm.

In terms of other biomarkers still to be studied, there have been studies examining next-generation sequencing. They haven’t found anything specific, but there is more work being done.

Which upcoming studies and treatment approaches in the field are you the most excited about?

An interesting study in the localized setting is the phase 3 ECOG-ACRIN EA2165 trial [NCT03233711], which is adding nivolumab after chemoradiation. It’s due to report later this year or next year, and those data will be informative. That’s an [approximately] 300-patient study and it will be interesting to understand whether adding immunotherapy in the localized setting after chemoradiation is beneficial. There are a number of [other] studies looking at combining immunotherapy with chemoradiation. Those will be informative, although some of them have changed [some] components, so interpreting those [data] might be challenging.

The other interesting approaches in this cancer have been the vaccine studies. There are a number of vaccine studies targeting HPV oncoproteins and some of those albeit smaller [trials] look interesting. We’re seeing some intriguing responses there. Combining vaccines with checkpoint inhibitors [also] seems to be an interesting approach. There are [several] trials yet to report which I believe will give us some important data.

There are many more trials than there used to be [which is] a real plus. A big issue is that we need more data on patient outcomes. There are a lot of consequences to pelvic radiotherapy and a lot of patients are living with different symptoms. The next tranche of trials is looking at trying to improve patient-reported outcomes.

In the localized setting, [investigators are examining] decreasing the doses of radiotherapy to try to help with long term outcomes or increasing radiotherapy in patients with worsening disease. The only way we’re going to improve outcomes for this cancer is to put as many patients into clinical trials [as possible], to identify them [quickly], and to give them a voice so we can understand what the important [remaining] questions are for us [to investigate].

Reference

1. Rao S, Samalin-Scalzi E, Evesque L, et al. POD1UM-303/InterAACT 2: phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (Pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (Chemo). Ann Oncol. 2024;35(suppl 2):S1217. doi:10.1016/j.annonc.2024.08.2262