Immunotherapy, Targeted Therapy, and Novel Strategies Progress Practice in GI Malignancies


Data that were presented during the 2021 ASCO Annual Meeting shed light on new therapeutic strategies, and treatment considerations that are expanding the paradigms of gastrointestinal malignancies.

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD

Data that were presented during the 2021 ASCO Annual Meeting shed light on new therapeutic strategies, and treatment considerations that are expanding the paradigms of gastrointestinal (GI) malignancies, such as colorectal cancer (CRC), biliary tract cancer, hepatocellular carcinoma (HCC), and upper GI cancers, said Yelena Y. Janjigian, MD, who added that checkpoint inhibitors, in particular, have been solidified as relevant options for many patients.

Colorectal Cancer

On June 29, 2020, the FDA approved pembrolizumab (Keytruda) for the frontline treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) CRC.1 The regulatory decision was based on findings from the phase 3 KEYNOTE-177 trial (NCT02563002), in which treatment with pembrolizumab induced a 40% reduction in the risk of disease progression or death vs standard chemotherapy in this patient population (HR, 0.60; 95% CI, 0.45-0.80; P =.0002).2 At a median follow-up of 32.4 months, the median progression-free survival (PFS) was 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2), respectively.

Updated findings from the study demonstrated that the median time from randomization to progression on next-line therapy or any-cause death (PFS2) was 54 months (95% CI, 44.4-not reached) with pembrolizumab vs 24.9 months (95% CI, 16.6-32.6) with chemotherapy.3 The 12-month PFS2 rates were 76% vs 67%, respectively. The 36-month PFS2 rates were 60% vs 39%, respectively.

“It is interesting that in the first-line setting, even with MSI-H tumors, a subset of patients progress very quickly on first-line immunotherapy,” said Janjigian, a medical oncologist and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in a virtual presentation during the 2021 ASCO Direct HighlightsTM webcast in New York, a program developed by Physicians’ Education Resource® LLC.

“Only after 8 or 9 months do the curves start to split in favor of immunotherapy again. This suggests that subsets of tumors—perhaps BRAF[-mutant] tumors or [patients with] more aggressive biologies with peritoneal disease––progress more quickly [with immunotherapy than] targeted therapy,” Janjigian added.

Despite a high crossover rate, the results of the trial highlighted that pembrolizumab was better tolerated, more convenient, and associated with improved health-related quality of life (QOL) in patients compared with chemotherapy.

In the maintenance setting for CRC, findings from the randomized FOCUS4-N trial (ISRCTN#90061546) affirmed that capecitabine is a reasonable maintenance therapy option for patients with metastatic CRC (mCRC). The median PFS was 3.84 months (Interquartile range [IQR], 2.17-7.39) with capecitabine maintenance compared with 1.87 months (IQR, 1.64-3.65) with active surveillance in the intention-to-treat population of patients with mCRC (adjusted HR, 0.38; 95% CI, 0.28-0.51; P < .0001).4 The median overall survival (OS) was 14.8 months (IQR, 10.2-21.8) vs 15.2 months (IQR, 8.8-24), respectively (HR, 0.93; 95% CI, 0.69-1.27; P = .66).

Although the OS was not significantly different between capecitabine and active surveillance, the study was “grossly underpowered” to demonstrate such a difference, Janjigian explained.

Notably, although cumulative toxicity was increased with capecitabine vs active surveillance, patient-reported QOL did not differ significantly between arms.

“[Maintenance therapy with capecitabine] is certainly a reasonable strategy to discuss with your patients,” Janjigian said.

Regarding targeted therapy in HER2-positive CRC, the final results of the phase 2 DESTINY-CRC01 trial (NCT03384940) showed that the median PFS with fam-trastuzumab deruxtecan-nxki (Enhertu) was 6.9 months (95% CI, 4.1-8.7) in patients with HER2 immunohistochemistry (IHC) 3+ or IHC2+/in situ hybridization (ISH)–positive mCRC, 2.1 months (95% CI, 1.4-4.1) in patients with HER2 IHC2+/ISH-negative mCRC, and 1.4 months (95% CI, 1.3-2.1) in patients with HER2 IHC1+ mCRC.5 The median OS was 15.5 months (95% CI, 8.8-20.8), 7.3 months (95% CI, 3.0–not evaluable [NE]), and 7.7 months (95% CI, 2.2-13.9), respectively.

Overall, 8 patients (9.3%) developed any-grade interstitial lung disease (ILD) with trastuzumab deruxtecan. Of these cases, 4 (4.7%) were grade 2, 1 (1.2%) was grade 3, and 3 (3.5%) were grade 5. Notably, the time-to-onset of fatal ILD varied, with a median time of 22 days (range, 9-120).

“It is important to consider starting [trastuzumab deruxtecan] early on and to do routine testing for IHC3+,” Janjigian added. “We are so used to doing next-generation sequencing on patients to know their RAS status, but IHC often comes back sooner and could be perhaps acted upon.”

Biliary Tract Cancer and Hepatocellular Carcinoma

In biliary tract cancer, the results of the phase 2b NIFTY trial (NCT03524508) demonstrated significant improvement in blinded independent central review (BICR) and investigator-assessed PFS, OS, and investigator-assessed overall response rate (ORR) with liposomal irinotecan (Nal-IRI) plus 5-fluorouracil and leucovorin in patients with metastatic disease following progression on gemcitabine plus cisplatin.6

Moreover, the PFS and OS improvements with Nal-IRI plus chemotherapy were observed across evaluable subgroups.

“Given that the study was conducted in [South] Korea only, global generalization of the data may be limited. It may not be quite practice changing, but it is certainly something to consider after gemcitabine/cisplatin progression,” Janjigian said.

In HCC, findings from the phase 3 FOHAIC-1 trial (NCT03164382) exhibited superior efficacy with hepatic arterial infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) compared with sorafenib (Nexavar) in patients with advanced disease.7 The median OS was 13.9 months (95% CI, 10.6-17.2) vs 8.2 months (95% CI, 7.5-9), respectively (HR, 0.408; 95% CI, 0.301-0.553; P < .001).

“[HAIC-FO] is not something that can be done at any center, so the applicability of these data is limited,” Janjigian said. “[Moreover,] for most of our patients [with advanced HCC] without varices and comorbidities, we now use the combination of bevacizumab [Avastin] and atezolizumab [Tecentriq].”

Upper Gastrointestinal Malignancies

Updated results of the phase 3 CheckMate 577 trial (NCT02743494) demonstrated a 31% reduction in the risk of recurrence or death and a doubling in median disease-free survival (DFS) with adjuvant nivolumab (Opdivo) vs placebo in patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation.8 The median DFS was 22.4 months (95% CI, 16.6-34) vs 11 months (95% CI, 8.3-14.3), respectively (HR, 0.69; 95% CI, 0.56-0.86; P = .0003).

The median PFS2 was not reached (95% CI, 34-NE) with nivolumab compared with 32.1 months (95% CI, 24.2-NE) with placebo (HR, 0.77; 95% CI, 0.60-0.99).

“It is important to consider [nivolumab] in the adjuvant setting, and I argue that these data are practice changing,” Janjigian said.

Also regarding nivolumab, initial results from the phase 3 CheckMate 648 trial (NCT03143153) demonstrated that at a minimum follow-up of 12.9 months, the median OS was 13.2 months (95% CI, 11.1-15.7) with nivolumab plus chemotherapy compared with 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone in the overall patient population (HR, 0.74; 95% CI, 0.58-0.96; P = .0021).9 In patients with tumor cell PD-L1 positivity of 1% or greater, the median OS was 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10), respectively (HR, 0.54; 95% CI, 0.37-0.80; P < .0001).

“It will be interesting to see how these data play out. Looking at biomarker selection and long-term survivors will help us delineate how to best use these agents,” said Janjigian.

Finally, interim findings from the ongoing phase 3 MK-3475-811/KEYNOTE-811 trial (NCT03615326) demonstrated an ORR of 74.4% (95% CI, 66.2%-81.6%) with pembrolizumab compared with 51.9% (95% CI, 43%-60.7%) with placebo (P = .00006) in patients with HER2-positive metastatic gastric or GEJ cancer.10 Complete responses were observed in 11% (n = 15) of patients who received pembrolizumab (n = 133) vs 3% (n = 4) patients who received placebo (n = 131); partial responses were observed in 63% (n = 84) vs 49% (n = 64) of patients, respectively.

These findings led the FDA to grant an accelerated approval to pembrolizumab in combination with trastuzumab (Herceptin), fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.11

“It was very satisfying to be able to bring this combination [to patients] in a relatively quick way based on the ORR [data]. Certainly, the FDA will look for the definitive event-free survival and OS data, which we will be presenting as soon as it is available,” Janjigian concluded.


  1. FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. News release. FDA. June 29, 2020. Accessed August 4, 2021.
  2. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699
  3. Andre T, Shiu KK, Kim TW, et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(suppl 15):3500. doi:10.1200/JCO.2021.39.15_suppl.3500
  4. Adams R, Fisher D, Graham J, et al. Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: results from the randomized FOCUS4-N trial. J Clin Oncol. 2021;39(suppl 15):3504. doi:10.1200/JCO.2021.39.15_suppl.3504
  5. Yoshino T, Di Bartolomeo MD, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2021;39(suppl 15):3505. doi:10.1200/JCO.2021.39.15_suppl.3505
  6. Yoo C, Kim KP, Kim I, et al. Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic biliary tract cancer (BTC) after progression on gemcitabine plus cisplatin (GemCis): multicenter comparative randomized phase 2b study (NIFTY). J Clin Oncol. 2021;39(suppl 15):4006. doi:10.1200/JCO.2021.39.15_suppl.4006
  7. Lyu N, Zhao M. Hepatic arterial infusion chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase 3 trial (The FOHAIC-1 study). J Clin Oncol. 2021;39(suppl 15):4007. doi:10.1200/JCO.2021.39.15_suppl.4007
  8. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): expanded efficacy and safety analyses from CheckMate 577. J Clin Oncol. 2021;39(suppl 15):4003. doi:10.1200/JCO.2021.39.15_suppl.4003
  9. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J Clin Oncol. 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001
  10. Janjigian YY, Kawazoe A, Yanez PE, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl 15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013
  11. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed August 4, 2021.
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