Earlier Use of Immunotherapy Combinations Explored in Esophageal Cancer

Ali Zaidi, MD

The commencement of new clinical trials and a handful of immunotherapy approvals have marked major advances in esophageal cancer over the past few years. Over this short span, the FDA granted a total of 5 practice-defining approvals based on the readouts from CheckMate 577 (NCT02743494), 648 (NCT03143153) and 649 (NCT02872116) and KEYNOTE-590 (NCT03189719) and -811 (NCT03615326) that essentially moved immunotherapies into the adjuvant space for resectable disease and first-line indications for advanced metastatic disease.

Most recently in May 2022, nivolumab (Opdivo) combinations were approved based on the phase 3 CheckMate 648 study, whose findings showed nivolumab plus ipilimumab (Yervoy) and nivolumab plus chemotherapy had statistically significant survival advantage.¹ In May, 2021, the FDA granted one of the first practice-defi ning approvals to adjuvant nivolumab as a treatment option for patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy (CRT) based on the CheckMate 577 trial.²

However, marginal readouts from trials occur as well. Some of these trials include the phase 3 ATTRACTION-4 study (NCT02746796) of nivolumab added to chemotherapy in patients with previously unmanaged advanced or recurrent gastric and GEJ cancers, and the phase 3 KEYNOTE-062 trial (NCT02494583) of pembrolizumab (Keytruda) with or without chemotherapy in the same population.

In an interview with Targeted Therapies in Oncology™, Ali Zaidi, MD, medical director of Esophageal & Lung Research at Allegheny Health Network and associate professor of surgery at Drexel University School of Medicine, discussed how the treatment landscape for patients with esophageal cancer has evolved over previous years and what research aims to look at in the near future.

Targeted Therapies in Oncology™: Can you discuss some of the recent approvals in the esophageal space?

ZAIDI: Until early 2021, the focus of treatment for locally advanced disease consisted of a couple of perioperative chemotherapy options, and neoadjuvant chemoradiation followed by surgery. In the metastatic setting, approaches were mostly palliative chemotherapy, other than the targeted agents trastuzumab [Herceptin], trastuzumab deruxtecan [Enhertu], and ramucirumab [Cyramza] approved for gastroesophageal adenocarcinoma subtype. We didn’t have much excitement in the potential ways to treat patients, but 2021 changed things with KEYNOTE-590. It demonstrated that pembrolizumab had decent activity for GEJ and esophageal cancer and the most pronounced activity was seen in patients with ESCC and/or a CPS greater than 10.3 That was followed by the adjuvant readout from KEYNOTE-577 [NCT02743494], which, for resectable disease, was extremely exciting.

After KEYNOTE-590, there was the CheckMate 649 trial, which was another exciting trial where we were seeing a great amount of activity again. Firstline nivolumab plus chemotherapy was evaluated vs chemotherapy alone. The trial was different from KEYNOTE-590 as it included patients with gastric cancer and excluded squamous histology.

Findings favored the combination in median overall survival [OS], and those patients with a CPS score greater than 5 were doing well.

The trial registered an impressive OS benefi t of 14.4 months for nivolumab and chemotherapy vs 11.1 months with chemotherapy alone. These 2 trial readouts led to broad FDA approvals establishing immunotherapy combined with chemotherapy as the new standard of care in the fi rst-line setting. Finally, CheckMate 648 data led to an FDA approval for adding nivolumab to fi rst-line chemotherapy and nivolumab and ipililumab as a nonchemotherapy option for metastatic ESCC.

In patients with a tumor proportion score (TPS) of 1% or greater, this trial demonstrated an OS of 15.2 months in the nivolumab/ chemotherapy arm and 13.7 months in the nivolumab/ipilimumab arm vs 9.1 months in the chemotherapy alone arm.

Adding pembrolizumab to trastuzumab treatment with chemotherapy in previously untreated locally advanced unresectable or metastatic HER2-positive gastroesophageal adenocarcinoma patients. An interim analysis demonstrated an overall response rate of 74% with the addition of pembrolizumab vs 52% for placebo along with improvement in duration of response. In second or more lines, these patients can now benefi t from trastuzumab deruxtecan monotherapy.⁴

Prior to that you had a little activity in limited later line data sets. We had KEYNOTE 181 [NCT02564263] and KEYNOTE-180 [NCT02559687] in which we had a second-line approval for pembrolizumab for ESCC patients with a greater than 10 CPS score.^5,6 Nivolumab was approved in this setting based on the ATTRACTION-3 [NCT02569242] readout.⁷

The problem is that although these are encouraging readouts, there are defi nitely some coverage gaps to fill. If you look at the KEYNOTE-649 [NCT02872116] readout, based on CPS greater than 5, we saw activity. But when we looked at KEYNOTE-062 [NCT02494583] and ATTRACTION-4 data, they were marginal readouts. In KEYNOTE-062, the chemotherapy backbone and biomarker selection was different. In ATTRACTION-4 you had more of an Asian population, lack of biomarker selection, and it was a negative readout for OS. The key takeaway message is that we are seeing promising activity for immunotherapy, both for squamous and adenocarcinoma, but there is a lot of room to improve.

How do community oncologists make sense of this information and decide the best way to treat patients?

For metastatic disease, our best predictive indicator of response is based on the PD-L1 cutoffs. For adenocarcinoma, with the CheckMate 649 and KEYNOTE-590 data being strong for patient populations who have high CPS scores and are HER2-negative, that should be your fi rst line and one should be using those regimens as the standard of care.

Once they progress, then there are potential options of either using a ramucirumab with or without a taxane or chemotherapy alone as a second-line treatment. In cases for metastatic and second-line settings for microsatellite instability, you can also use pembrolizumab. After more than 2 lines, chemotherapy becomes your fallback option. For HER2- positive patients the KEYNOTE-811 regimen should be your go to strategy for previously untreated patients.

Squamous [cell cancer] is more interesting as you have pembrolizumab as an option. Additionally, CheckMate 648 regimens, nivolumab/ipilimumab or nivolumab/chemotherapy, are established as very promising options for patients with a TPS score greater than 1. In terms of median OS, nivolumab/chemotherapy showed overall better activity and should be offered in the first-line setting to immunotherapy-naive patients regardless of TPS status. The nivolumab/ipilimumab regimen may be used in select patients with contraindications to chemotherapy. Then if you go to second-line settings, based on KEYNOTE-180 and -181 [NCT02564263] data, for the squamous population with a greater than 10 CPS you can use pembrolizumab monotherapy, or one can use nivolumab based on the ATTRACTION-3 data. If that fails, there is always chemotherapy as a backup.

It is important to note that although the FDA approvals are overarching and don’t defi ne CPS or TPS cutoffs, patients with low PD-L1 scores are not likely to get the benefit. For these patients, clinical trials, including combination strategies targeting the tumor immune evasion mechanisms can be a great fit.

What ongoing research have you been examining?

The last few years have been great in terms of immunotherapy being incorporated into the treatment landscape, and the associated physician excitement. However, there’s a lot to be done, because the metastatic disease survival benefit is still limited to just over a year.

Our group, like others, has tried to build on these successful readouts by moving immunotherapy regimens to wider and earlier resectable disease settings.

We recently reported at the American Society of Clinical Oncology Annual Meeting data from CheckMate 906 [NCT03044613], a phase 2 study of neoadjuvant nivolumab or nivolumab/relatlimab plus chemoradiotherapy for resectable esophageal or gastroesophageal junction (E/GEJ) cancers. The addition of nivolumab to preoperative CRT was determined to be safe and is associated with a pCR of 38%. Notably, the nivolumab/ relatlimab arm was challenging due to enhanced immune-related toxicities with no addictive efficacy benefit. In this limited dataset we showed a median disease-free survival [DFS] of around 35 months which was in line with what we were seeing with the adjuvant CheckMate 577 readout. Such studies are key early efforts to produce ways to improve on the survival benefit or try to move it in earlier settings where you can have curative intent associated with these, including longer DFS.

Additionally, even with targeted therapies we are seeing a lot of interesting signals show up within specific populations, and that’s where we need to view these diseases as molecularly independent, as well as going after those small mutations that could potentially be relevant. There is DKN-01, which is a DKK1 antibody targeting the WNT signaling mechanisms and there is some early promising data from the DisTinGuish study [NCT04363801], a phase 2 trial. Then you have Claudin 18.2, which is an interesting target expressed in upper gastrointestinal cancers, targeted in the GLOW trial [NCT03653507] with monoclonal antibodies. Monotherapy as well with chemotherapy showed some early activity. Also you have antibodies targeting FGFR, type 2b receptors, that have shown promising activity in smaller studies as well. All in all, there is a lot more to play around with than what we had for the last decade or so.

What questions still need to be answered in this space?

With immunotherapy now widely used in the esophageal cancer setting we need to develop and improve existing biomarkers for selecting personalized treatments in patients that will be safe, efficacious, and cost effective. Moreover, with these newly established immunotherapybased standard-of-care regimens it is critical to refresh the active and future clinical trial designs to unlock addictive benefit from promising combination strategies, especially ones targeting immune evasion mechanisms.

_REFERENCES

_{1. FDA approves nivolumab for resected esophageal or GEJ cancer. News release. Accessed October 11, 2022. https://bit.ly/3VcP8Qh}

_{2. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. News release. Accessed October 10, 2022. https://bit.ly/3rMQ3t9}

_{3. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4}

_{4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated her2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430. doi:10.1056/NEJMoa2004413}

_{5. Kojima T, Shah MA, Muro K, Francois E, et al. KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. doi: 10.1200/JCO.20.01888.}

_{6. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. News release. Accessed October 19, 2022. https://bit.ly/3MMNLUr}

_{7. FDA approves nivolumab for esophageal squamous cell carcinoma. News release. Accessed October 19, 2022. https://bit.ly/3D6V3zh}