NCCN Guidelines for Gastric and Esophageal Cancers Updates Encompass Immunotherapy, TKIs Across Settings

Crystal S. Denlinger, MD

Key updates to the National Comprehensive Cancer Network (NCCN) guidelines for gastric and esophageal cancers include the incorporation of immune checkpoint inhibitors spanning settings in patients with gastroesophageal cancer, the inclusion of fam-trastuzumab deruxtecan-nxki (Enhertu) for those with HER2-positive gastric cancer, and the addition of recommended ramucirumab (Cyramza) combinations for use in second- or later-line settings.¹

Notable revisions include:

• The addition of nivolumab (Opdivo) after preoperative chemoradiation with R0 resection and residual disease as a category 1 preferred regimen in localized esophageal and esophagogastric junction cancers
• The addition of several frontline immunotherapy regimens for HER2-negative esophageal and esophagogastric junction cancers, such as: fluoropyrimidine, oxaliplatin and nivolumab in those with a PD-L1 combined positive score (CPS) of 5 or greater (category 1); fluoropyrimidine, oxaliplatin, and pembrolizumab (Keytruda) in those with a PD-L1 CPS of 10 or greater; and fluoropyrimidine, cisplatin, and pembrolizumab for those with a PD-L1 CPS of 10 or greater (category 1)
• The addition of fluoropyrimidine, oxaliplatin, and nivolumab for those with gastric cancer who have a PD-L1 CPS of 5 or greater (category 1)
• The addition of nivolumab as a preferred category 1 second-line treatment for patients with esophageal squamous cell carcinoma (ESCC)
• The addition of pembrolizumab as a preferred category 1 second-line treatment for ESCC with a PD-L1 CPS of 10 or higher
• The addition of trastuzumab deruxtecan for second-line treatment of HER2 overexpression–positive esophageal/GEJ metastatic adenocarcinoma and as a preferred second-line treatment for HER2 overexpression–positive gastric metastatic adenocarcinoma

In a presentation during the NCCN 2021 Virtual Annual Conference, Crystal S. Denlinger, MD, of Fox Chase Cancer Center; Kristina A. Makowskyj, MD, PhD, of the University of Wisconsin Carbone Cancer Center (UWCCC); and Mary F. Mulcahy, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, walked through the latest changes made to the guidelines, the recent data that have served to support those decisions, and the growing role of biomarkers in guiding treatment decisions.

“This is an exciting time to be a medical oncologist who treats not only [patients with] gastrointestinal cancers, but gastroesophageal cancer. I think it’s safe to say that biomarkers are going to be key for categorizing our patients,” said Denlinger, who is chief of the Division of Gastrointestinal Medical Oncology, director of the Survivorship Program, deputy director of the Early Clinical Drug Development Phase 1 Program, and associate professor in the Department of Hematology/Oncology at Fox Chase. “The bare minimum that needs to be ordered at a new diagnosis includes microsatellite status, HER2 status, and PD-L1 status.”

Biomarker and Next-Generation Sequencing Considerations

Biomarker testing can be performed on a formalin-fixed, paraffin embedded tissue; however, these tissues must be held for a minimum of 10 years, unless the tissue is being exhausted for diagnostic purposes or for clinical trial enrollment. “As such, we’re always able to go back to the tissue that was obtained from that patient should new biomarkers arise,” noted Matkowskyj, who is the director of Translational Science BioCore and associate director of the Translational Research Initiatives Laboratory in the Department of Pathology and Laboratory Medicine at UWCCC.

Matkowskyj, who is also an associate professor in the Department of Pathology and Laboratory Medicine at the University of Wisconsin School of Medicine and Public Health and staff pathologist at the William S. Middleton VA Medical Center, added that it is important to ensure that tissue is being sent to a CLIA-approved laboratory for testing. Biomarkers that need to be tested for include HER2 per immunohistochemistry (IHC), microsatellite instability (MSI) via a polymerase chain reaction (PCR) test or mismatch repair protein expression via IHC, and PD-L1 expression via IHC.

Although next-generation sequencing (NGS) provides the opportunity to evaluate several mutations at once, as well as other molecular effects like amplification, deletions, tumor mutational burden [TMB], and MSI status, it is not without limitations. As such, “testing should always be first performed by those gold-standard methods [of IHC and in situ hybridization],” noted Matkowskyj. If abundant tissue is available, then the initial tests can be performed, and they can be followed by NGS.

Full NGS profiling may be appropriate when limited tissue is available or biopsy is not possible. However, Denlinger warned that with limited tumor samples, it is important to be careful and consider whether full profiling should be used vs just individual biomarkers.

“New within the guidelines is that all gastric cancers should now be tested for MSI up front, at the time of diagnosis,” noted Matkowskyj; this can be done through the use of IHC or PCR.

Adding Immunotherapy to Frontline Gastric, GEJ, Esophageal Adenocarcinoma

Immune checkpoint inhibitors can now be considered for use in combination with platinum/fluoropyrimidine in the frontline treatment of patients with gastroesophageal cancer who have a high CPS, based in part, on data from the phase 3 CheckMate-649 trial (NCT02872116).²

In the study, previously untreated patients with unresectable, advanced, or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma with no known HER2-positive status and an ECOG performance status of 0 or 1 were randomized 1:1:1 to either nivolumab plus ipilimumab (Yervoy), nivolumab plus XELOX or FOLFOX per provider decision, or XELOX or FOLFOX.

“We’re just going to look at the randomized study of nivolumab plus chemotherapy [n = 789] vs chemotherapy alone [n = 792],” noted Mulcahy, who is a professor in the Department of Hematology/Oncology at Northwestern University and director of the Gastrointestinal Oncology Program at the Robert H. Lurie Comprehensive Cancer Center. “Notably, this did not include the squamous cell population; this is all adenocarcinomas.”

The dual primary end points of the trial were overall survival (OS) and progression-free survival (PFS) for patients with a PD-L1 CPS of greater than 5%.

Results indicated that nivolumab plus chemotherapy significantly improved median OS over that of chemotherapy arm. The median OS was 14.4 months (95% CI, 13.1-16.2) in the investigative arm vs 11.1 months (95% CI, 10.0-12.1) in the control arm (HR, 0.71; 95% CI, 0.59-0.86; P <.0001).

“What’s interesting in this study is that it just so happens that more than 60% of patients had a CPS of greater than 5, and more than 80% had a CPS of greater than 1, so this was somewhat of an enriched population for PD-L1 expression,” Mulcahy said.

In patients who had a PD-L1 CPS of 1 or greater, the median OS still favored the nivolumab regimen over chemotherapy alone, with a median OS of 14.0 months (95% CI, 12.6-15.0) vs 11.3 months (95% CI, 10.6-12.3), respectively (HR, 0.77; 95% CI, 0.64-0.92; P = .0001). In all randomized patients, the HR was 0.80 (95% CI, 0.68-0.94; P = .0002).

The nivolumab-containing regimen also resulted in an improvement in objective response rate (ORR) over chemotherapy alone, at 60% (95% CI, 55%-65%) vs 45% (95%, 40%-50%), respectively (P <.0001). The duration of response (DOR) was also maintained for those on the nivolumab arm at 9.5 months vs 7.0 months for those on chemotherapy.

“Nivolumab is the first PD-1 inhibitor to demonstrate a superior response, PFS, as well as DOR, when compared with chemotherapy,” Mulcahy said. “As such, nivolumab plus chemotherapy presents a new standard-of-care first-line therapy for patients with adenocarcinoma and gastric cancer with a PD-L1 CPS of greater than or equal to 5.”

Adding Immunotherapy to Frontline Advanced Esophageal Cancer

In the phase 3 KEYNOTE-590 trial (NCT03189719), treatment-naïve patients with locally advanced, unresectable or metastatic esophageal adenocarcinoma or ESCC or esophagogastric junction Siewert type 1 adenocarcinoma with an ECOG performance status of 0 or 1 and measurable disease were randomized 1:1 to receive either pembrolizumab and chemotherapy with 5-fluorouracil (5-FU) and cisplatin or placebo and chemotherapy.³

“Patients enrolled to this study had esophageal adenocarcinoma or squamous cell cancer; this was specifically an esophageal study, but it included both histologies,” Mulcahy noted. “No specification about PD-L1 expression [was made] for this study for enrollment purposes or stratification. Another thing to point out is that the chemotherapy backbone used in this study is not commonly used for most of us in practice. Many have switched to an oxaliplatin-based therapy; it’s better tolerated.”

The dual primary end points of the trial included OS and PFS per RECIST v1.1 criteria and investigator assessment, while ORR per the same criteria served as the secondary end point.

Notably, 73.5% of patients on the pembrolizumab arm and 72.9% of those on the chemotherapy-alone arm had squamous histology, which is not a common histology in the United States, noted Mulcahy. About half of the patients enrolled had a PD-L1 CPS of greater than 10, “so this was a very rich population for a high PD-L1 expression,” noted Mulcahy.

The addition of pembrolizumab to the chemotherapy backbone was found to significantly improve OS in patients with a PD-L1 CPS of 10 or higher. In these patients, the median OS was 13.5 months (95% CI, 11.1-15.6) and 9.4 months (95% CI, 8.0-10.7) in the investigative and control arms, respectively (HR, 0.62; 95% CI, 0.49-0.78; P <.0001). The pembrolizumab-containing regimen was also found to improve OS over chemotherapy alone in all patients (HR, 0.73; 95% CI, 0.62-0.86; P <.0001).

A “striking difference” in OS was also observed in the patients specifically with ESCC who had a PD-L1 CPS of 10 or higher. In this subset, the median OS was 13.9 months (95% CI, 11.1-17.7) in the pembrolizumab arm vs 8.8 months (95% CI, 7.8-10.5) in the chemotherapy-alone arm (HR, 0.57; 95% CI, 0.43-0.75; P <.0001). OS in all patients with ESCC also favored the pembrolizumab-containing regimen (HR, 0.72; 95% CI, 0.60-0.88).

A benefit in terms of ORR and DOR was also observed with pembrolizumab/chemotherapy vs chemotherapy alone. The ORRs in the investigative and control arms were 45.0% (95% CI, 39.9%-50.2%) vs 29.3% (95% CI, 24.7%-34.1%), respectively (P <.0001); the median DORs were 8.3 months and 6.0 months, respectively.

“These data support the use of pembrolizumab with chemotherapy for all [patients with] esophageal cancer and [PD-L1] CPS of greater than 10,” said Mulcahy. “However, the most striking difference was seen in [those] with squamous cell [disease].”

HER2-Positive Disease: Examining Promises and Pitfalls

“We have previously been disappointed in our second-line, HER2-directed treatment options,” admitted Denlinger. “This is clearly not the same as what has been seen in breast cancer, where HER2-directed therapy across lines of treatment has been effective.”

For instance, although data from the phase 3 TyTAN trial, which examined second-line paclitaxel with or without lapatinib (Tykerb) in Asian patients with HER2-amplified, advanced gastric cancer, demonstrated activity in patients with HER2 FISH-positive IHC3+ advanced disease, it did not significantly improve OS in the intent-to-treat population.⁴

Additionally, findings from the phase 2/3 GATSBY trial (NCT01641939), which evaluated second-line ado-trastuzumab emtansine (Kadcyla; T-DM1) vs physician’s choice of paclitaxel or docetaxel in those with HER2-positive advanced gastric cancer, failed to show superiority with T-DM1 over taxane treatment.⁵ Lastly, the phase 2 T-ACT trial (UMIN000009297), which looked at second-line paclitaxel with or without trastuzumab (Herceptin) in patients with HER2-positive advanced gastric or GEJ cancer, demonstrated that the addition of trastuzumab was not superior.⁶

“Up until recently, we had no data [to support] HER2-directed therapy after progression on trastuzumab and this may be due to the fact that HER2 expression can change after trastuzumab,” noted Denlinger.

Trastuzumab Deruxtecan Changes the Game

Despite these challenges, the antibody-drug conjugate (ADC) trastuzumab deruxtecan has emerged in the paradigm and received FDA approvalin January 2021 for use in adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have previously received a trastuzumab-based regimen, based on data from the phase 2 DESTINY-Gastric01 trial (NCT04014075).⁷

“It’s an ADC that has been optimized to try and get delivery of the cytotoxic drug to the tumor cell and it has a pretty high drug to antibody ratio of 8:1,” said Denlinger. “The other neat thing about this particular drug is that the cytotoxic agent can diffuse across cell membranes to neighboring cells to create a bystander effect.”

In DESTINY-Gastric01, 188 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had progressed on a trastuzumab-based regimen and received 2 or more previous regimens including fluoropyrimidine/platinum, were randomized 2:1 to receive either the ADC (n = 126) or physician’s choice of chemotherapy in the form of irinotecan (n = 55) or paclitaxel (n = 7).

Trastuzumab deruxtecan significantly improved OS over chemotherapy, at 12.5 months (95% CI, 9.6-14.3) and 8.4 months (95% CI, 6.9-10.7), respectively (HR, 0.59; 95% CI, 0.39-0.88; P = .01); the ADC also improved PFS over chemotherapy, at 5.6 months (95% CI, 4.3-6.9) vs 3.5 months (95% CI, 2.0-4.3), respectively (HR, 0.47; 95% CI, 0.31-0.71.

Moreover, trastuzumab deruxtecan elicited an ORR of 51% (95% CI, 42%-61%) vs 14% (95% CI, 6%-26%) with chemotherapy. “For those of us who have seen a lot of gastroesophageal cancer, patients [in the third-line setting] do not typically get a response to therapy, so 51% is a very clinically meaningful number,” noted Denlinger.

Eighty-six percent of patients in the investigative arm achieved disease control vs 62% of those in the control arm.

However, the agent is not without toxicity; adverse effects can include nausea, vomiting, cytopenias, alopecia, and fatigue. Notably, interstitial lung disease or pneumonitis was found to have occurred in 10% of patients, with a median time to onset of 84 days and a median time to resolution of 57 days.

“The package insert specifically states to initiate corticosteroid therapy at grade 1 and to discontinue the drug at grade 2 and use higher doses of steroids,” explained Denlinger. “This is something that really needs to be though about because the median onset is long, approximately 3 months, and the median time to resolution is approximately 2 months. We need to ensure that we monitor for this and consider early initiation of corticosteroids if this effect is suspected.”

Examining Other Second-Line Options

Single-agent ramucirumab or in combination with paclitaxel has proven to be an effective second-line treatment option for patients with advanced gastroesophageal adenocarcinoma and an increasing number of patients are pretreated with docetaxel in the perioperative or frontline setting.

In the phase 2 RAMIRIS trial (NCT033081143), patients with advanced or metastatic gastroesophageal adenocarcinoma who previously received treatment with a fluoropyrimidine/platinum-containing regimen were randomized 2:1 to receive either FOLFIRI plus ramucirumab or paclitaxel plus ramucirumab.⁸ The end points of the trial included OS, ORR, disease control rate (DCR), PFS, and toxicity.

The ORR achieved with FOLFIRI/ramucirumab was 22% (n = 16/72) vs 11% (n = 4/38) with paclitaxel/ramucirumab; in docetaxel-pretreated patients, these rates were 25% (n = 12/48) and 8% (n = 2/24), respectively. The DCR rates in the FOLFIRI and paclitaxel arms were 61% (n = 44/72) and 58% (n = 21/38), respectively; in docetaxel-pretreated patients, these rates were 65% (n = 31/48) and 37% (n = 9/24), respectively.

“A larger phase 3 trial is looking at this to confirm the benefit, but certainly FOLFIRI plus ramucirumab is an option for patients in whom a taxane-based treatment option is not ideal,” said Denlinger.

Additionally, the phase 3 KEYNOTE-061 trial (NCT02370498) compared pembrolizumab with paclitaxel in patients with previously treated, advanced gastric or GEJ cancer with a PD-L1 CPS of 1 or higher.^9,10 Results showed pembrolizumab did not significantly improve OS vs paclitaxel as second-line treatment in this population.

“This was a negative trial but there are some subpopulations in which immunotherapy might be an option and certainly looking at the OS curves from the original study, the benefit of therapy seems to be greatest in the [patients with] a PD-L1 CPS of greater than 10,” noted Denlinger. “However, subset analyses from the study suggest that the population that maybe will benefit the most from it are the MSI high (MSI-H) patients…a similar subset analysis suggested that in patients who had a high TMB, pembrolizumab performed better than paclitaxel.”

Traversing Into Third-Line or Later Treatments

In the phase 2 KEYNOTE-059 trial, investigators examined the safety and efficacy of single-agent pembrolizumab in 259 patients with previously treated advanced gastric or gastroesophageal junction cancer.¹¹ Results indicated the ORR achieved with the immunotherapy was 11.6% (95% CI, 8.0%-16.1%), with 2.3% of patients achieving a complete response. The median DOR was 8.4 months.

Patients who had PD-L1–positive tumors favored even better with the therapy, with an ORR of 15.5% (95% CI, 10.1%-22.4%) and a median DOR of 16.3 months. Those with PD-L1 negativity still derived benefit, with an ORR of 6.4% (95% CI, 2.6%-12.8%) and a DOR of 6.9 months.

“When you look deeper into the study, you do find that those who are PD-L1 positive did have a greater response rate than those who were PD-L1 negative; this did translate to an improvement in OS,” Mulcahy noted. “…I think study after study we’re finding out that those with the higher PD-L1 expression are more likely to derive benefit from it.”

In the phase 3 TAGS trial (NCT02500043), investigators set out to evaluate the efficacy and safety of trifluridine/tipiracil (TAS-102; Lonsurf) plus best supportive care (BSC) vs best BSC alone in patients with heavily pretreated, metastatic gastric cancer.^12,13 Results showed a significant OS benefit with TAS-102 at 5.7 months vs 3.6 months with BSC (HR, 0.69; 95% CI, 0.56-0.85; P = .00058), although the PFS benefit was not determined to be significant, at 2.0 months and 1.8 months, respectively (HR, 0.57; 95% CI, 0.47-0.70; P <.0001).

“We now have options. I can remember a time where we really only had 1 line of therapy and now, we are talking about multiple lines of therapy, multiple different options, that can be then tailored to the individual patient,” Mulcahy said. “Certainly, this agent is an option in later lines of therapy, namely third line or later.”

Considerations for Adjuvant Nivolumab in Esophageal or GEJ Cancer

In the phase 3 CheckMate-577 trial (NCT02743494), patients with resected stage II/III esophageal or GEJ cancer who received neoadjuvant chemoradiation and had residual pathologic disease were randomized 2:1 to receive either nivolumab (n = 532) or placebo (n = 262), followed by nivolumab or placebo.¹⁴

“About 30% had squamous cell carcinoma and about 60% had adenocarcinoma,” Mulcahy noted. “The majority of patients had a PD-L1 expression of less than 1%, so we can think of the results that we see from this study as independent from what their PD-L1 expression is.”

The primary end point was disease-free survival (DFS), while secondary end points included OS and OS rate at 1, 2, and 3 years. Results showed that the median DFS with nivolumab was 22.4 months (95% CI, 16.6-34.0) vs 11.0 months (95% CI, 8.3-14.3) with nivolumab (HR, 0.69; 95% CI, 0.56-0.86; P = .0003).

“This is really the first study that has the most robust data we have showing any benefit with adjuvant therapy after resection for esophageal cancer,” Mulcahy said. “…It potentially establishes adjuvant nivolumab as a new standard of care.”

Final Thoughts

“We certainly know that for frontline therapy, immune checkpoint inhibitors can be considered,” Denlinger concluded. “Trastuzumab deruxtecan after trastuzumab-based frontline therapy is now an option for HER2-positive disease and now, we have multiple options in second or later lines of therapy for refractory disease so we can tailor our treatment regimens, not only to the particular disease characteristics but also to our patient characteristics. This is really an exciting time for this particular disease.”

References

1. Denlinger CS, Matkowskyj KA, Mulcahy MF, et al. NCCN guidelines updates: gastric and esophageal cancers. Presented at: NCCN 2021 Virtual Annual Conference; March 18-20, 2021; virtual. Accessed March 19, 2021.
2. Moehler M, Shitara K, Garrido M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. Ann Oncol. 2020;31(suppl 4):S1191. doi:10.1016/j.annonc.2020.08.2296
3. Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(suppl 4):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298
4. Satoh T, Xu R-H, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase II study. J Clin Oncol. 2014;32(19):2039-2049. doi:10.1200/JCO.2013.53.6136
5. Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640-653. doi:10.1016/S1470-2045(17)30111-0
6. Makiyama A, Sagara K, Kawada J, et al. A randomized phase II study of weekly paclitaxel +/- trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT). J Clin Oncol. 2018;36(suppl 15):4011. doi:10.1200/JCO.2018.36.15_suppl.4011
7. Shitara K, Bang Y-J, 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
8. Lorenzen S, Thuss-Patience PC, Pauligk C, et al. FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: results from the phase II RAMIRIS study of the AIO. J Clin Oncol. 2020;38(suppl 15):4514. doi:10.1200/JCO.2020.38.15_suppl.4514
9. Fuchs CS, Ozguroglu M, Bang Y-J, et al. Pembrolizumab (pembro) vs paclitaxel (PTX) for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer: phase 3 KEYNOTE-061 trial. J Clin Oncol. 2018;36(suppl 15):4062. doi:10.1200/JCO.2018.36.15_suppl.4062
10. Shitara K, Ozhuroglu M, Bang Y-J, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123-133. doi:10.1016/S0140-6736(18)31257-1
11. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013
12. Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018;19(11):1437-1448. doi:10.1016/S1470-2045(18)30739-3
13. Ilson DH, Tabernero J, Prokarau A, et al. Efficacy and safety of trifluridine/tipiracil treatment in patients with metastatic gastric cancer who had undergone gastrectomy: subgroup analyses of a randomized clinical trial. JAMA Oncol. 2019;6(1):e193531. doi:10.1001/jamaoncol.2019.3531
14. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. Ann Oncol. 2020;31(suppl 4):S1193-S1194. doi:10.1016/j.annonc.2020.08.2299