ASCO 2022 Meeting Report — Gastrointestinal Cancers

The 2022 American Society of Clinical Oncology (ASCO) annual meeting, held in Chicago June 3 to 7, highlighted important advances in treatment across a broad spectrum of gastrointestinal malignancies. Here, Associate Editor Dr. David H. Ilson reviews key trials. Meeting abstracts can be viewed in the ASCO meeting library.

Cercek and colleagues presented potentially practice-changing findings on use of the anti PD-1 agent dostarlimab as the primary treatment for MSI-high locally advanced rectal cancer (abstract LBA5). In the phase 2 trial, adults with stage II or III disease received intravenous dostarlimab (500 mg) alone every 3 weeks for 6 months, to be followed by chemoradiotherapy and total mesorectal surgery. Patients with a clinical complete response to dostarlimab could forego chemoradiotherapy and surgery.

Of the first 16 patients enrolled in this investigator-initiated protocol, 56% were T3, 94% were node positive, and 57% tested positive for germline mutations for DNA mismatch repair protein deficiency. Of 12 patients with at least 6 months' follow-up, 100% achieved a clinical complete response to dostarlimab therapy (assessed on serial endoscopy and biopsy, PET and CT scan, and rectal MRI) and none required chemotherapy, radiotherapy, or surgery.

The trial is ongoing but suggests that immune checkpoint inhibitor therapy may be considered as the initial treatment in patients with MSI-high rectal cancers, with chemoradiotherapy and surgery reserved as salvage options.

Read more about the study in the New England Journal of Medicine (N Engl J Med 2022; 386:2363) and in NEJM Journal Watch Oncology and Hematology and watch an interview with the lead author.

Tie and colleagues reported results of a phase 2 trial in which 441 patients with resected stage II colon cancer were randomized to selection for adjuvant chemotherapy based on either positive testing for circulating tumor DNA (ctDNA) at 4 and 7 weeks after surgery or conventional high-risk pathologic features (abstract LBA100).

High-risk features were present in 40% of patients. ctDNA testing was successful in 99% of patients, and nearly all ctDNA-positive patients received adjuvant chemotherapy (98%). Use of adjuvant chemotherapy was reduced by 50% in the ctDNA-guided group compared with the conventionally selected patients (15% vs. 28%). The primary endpoint, recurrence-free survival at 2 years, was equivalent for the two groups (93.5% and 92.4%; hazard ratio, 0.96), indicating that chemotherapy avoidance in the ctDNA-negative patients did not compromise outcome. Encouraging results were obtained for 3-year recurrence-free survival in the ctDNA-positive patients treated with oxaliplatin-based chemotherapy (92.6%) or single-agent fluoropyrimidine (76%).

Ongoing trials evaluating ctDNA to guide adjuvant therapy may lead to de-escalation of therapy in negative patients and escalation in positive patients.

Read more about the study in the New England Journal of Medicine (N Engl J Med 2022; 386:2261) and in NEJM Journal Watch Oncology and Hematology.

In the adjuvant setting, Hu and colleagues reported a phase 3 trial of 739 patients with radiographic clinical stage T3–4 colon cancer who were randomized to either 3 months of neoadjuvant chemotherapy with capecitabine/oxaliplatin or FOLFOX followed by surgery and 3 months of adjuvant chemotherapy, or upfront surgery followed by adjuvant chemotherapy dictated by the pathologic stage of the cancer (abstract 3500).

Rates of R0 resection were similar in the preoperative therapy and upfront surgery arms (97% and 95%). The preoperative therapy arm had a lower rate of pathologic T4 status (10% vs. 20%; P<0.001) and a higher rate of pathologic N0 status (69% vs. 54%; P<0.001). There was no difference between groups in the primary endpoint of 3-year disease-free survival (78.4% and 76.6%; P=0.16); however, in post hoc subgroup analysis, female patients had higher 3-year disease-free survival with preoperative therapy compared to upfront surgery (HR, 0.54; P=0.02).

These results indicate the safety and feasibility of preoperative compared to standard adjuvant therapy, with no clear improvement in 3-year disease-free survival and a potential benefit in female patients. The risk of preoperative chemotherapy is overtreatment of lower-risk stage II patients, given that 54% of the upfront surgery group had N0 disease.

In a plenary session Yoshino and colleagues presented findings from a phase 3 trial that randomized 823 patients with RAS wild-type metastatic colorectal cancer to treatment with either bevacizumab or the EGFR-targeted monoclonal antibody panitumumab plus first-line mFOLFOX6 chemotherapy (abstract LBA1). The primary endpoint was overall survival; other endpoints focused on left-sided primary tumors.

Of 802 patients included in the efficacy analysis, 75% had left-sided primary tumors, and in this group, 62% underwent resection of the primary tumor and 50% had two or more sites of metastases. Among patients with left-sided primary tumors, median overall survival was superior with panitumumab compared with bevacizumab (37.9 vs. 34.4 months; HR, 0.82; P=0.031), with the survival curves not clearly separating until beyond 24 months. Although a higher response rate was observed with panitumumab compared with bevacizumab (80.2% vs. 68.6%), there was no difference in median progression-free survival (13.7 and 13.2 months; HR, 0.98).

Findings from this trial add to existing data suggesting a late survival benefit for patients with left-sided RAS wild-type colorectal cancer receiving upfront treatment with an EGFR-targeted agent, without a progression-free survival benefit. The toxicities of initial EGFR-targeted therapy have to be weighed against these potential benefits.

Another phase 3 trial, presented by Cremolini and colleagues, compared the triplet regimen FOLFOXIRI against the doublet regimen FOLFOX, combined with panitumumab, in the first-line treatment of metastatic RAS and BRAF wild-type colon cancer (abstract LBA3505). Of 435 patients, 88% had left-sided primary tumors, 47% had the primary tumor resected, and 4% had received prior adjuvant chemotherapy.

There was no difference between the triplet and doublet arms in the primary outcome of overall response rate (73% and 76%; odds ratio, 0.87; P=0.526) or in achievement of R0 resection of metastatic disease (25% and 29%) or in progression-free survival (median, 12.3 and 12.7 months; HR, 0.88; P=0.277). The triplet arm had higher incidence of grade 3/4 neutropenia and diarrhea.

The trial indicates that in RAS and BRAF wild-type metastatic colorectal cancer, a triplet regimen should not be used over a doublet regimen for first-line treatment when combined with an EGFR-targeted agent.

Another important trial, reported by Rahbari and colleagues, addressed the role of resection of the primary tumor prior to chemotherapy in patients with unresectable metastatic colorectal cancer (abstract LBA3507). Among 393 patients randomized to chemotherapy alone or primary resection followed by chemotherapy, the most common metastasis sites were liver (95%) followed by lung (29%). Roughly half of patients received an oxaliplatin doublet regimen and one-third received an irinotecan doublet regimen; more patients received bevacizumab (40%) than an EGFR-targeted agent (21%); and more patients in the surgery arm than the chemotherapy-alone arm received no chemotherapy (24% vs. 6%).

There was no significant difference between the chemotherapy-alone and surgery groups in the primary endpoint of overall survival (median, 18.6 and 16.7 months). This important trial reinforces other findings from other recent randomized trials indicating that resection of the primary tumor in metastatic colon cancer does not improve survival.

Fietkau and colleagues reported results from a randomized phase 3 trial comparing the use of preoperative chemotherapy or chemotherapy combined with radiotherapy followed by attempted surgery in patients with borderline or unresectable pancreatic cancer (abstract 4008). Among 495 patients started on induction chemotherapy, FOLFIRINOX was the most common regimen given (81%), followed by single-agent gemcitabine (19%). Among the 336 patients continuing chemotherapy, half were randomized to continue chemotherapy or to receive weekly gemcitabine plus 5040 cGy of radiotherapy.

Of the randomized patients, only 122 (36%) underwent attempted surgery, with no difference between the chemotherapy and chemoradiotherapy arms. The chemoradiotherapy group had higher rates of R0 resection, (69% vs. 50), the primary endpoint, and of pathologic complete response (18% vs. 2%). However, in all randomized patients there was no difference between the chemoradiotherapy and chemotherapy groups in progression-free survival (median, 8 and 9 months; HR, 0.976) or overall survival (median, 15 months; HR, 0.975). In patients who underwent surgery, there was no difference in overall survival with or without radiotherapy (median, 19 and 20 months; HR, 0.896; P=0.61).

The negative results continue to fuel the debate about the role of radiotherapy in unresectable or borderline resectable pancreatic cancer.

A phase 2 trial evaluating use of trastuzumab deruxtecan to treat HER2-positive biliary cancers was reported by Ohba and colleagues (abstract 4006). Of 30 evaluable patients, 73% were HER2 positive by immunohistochemistry and fluorescence in situ hybridization and 27% were low HER2 expressors.

Responses occurred in 36.4% of HER2-positive patients and 12.5% of low expressors, with median progression-free survival of 5.1 months and 3.5 months, respectively. Grade ≥3 pneumonitis was reported in 12.5% of patients.

The signal of efficacy observed in both low and high HER2-expressing patients merits further study and continues to validate HER2 as a viable target in biliary cancers.

Lastly, Qin and colleagues presented a randomized placebo-controlled trial comparing gemcitabine with and without the addition of the EGFR-targeted agent nimotuzumab in the rare subset of patients with KRAS wild-type advanced pancreatic cancer (abstract LBA4011). Of 81 patients randomized, 79% had metastatic disease and 56% had undergone prior surgery.

Overall survival was modestly improved with nimotuzumab compared with placebo (median, 10.9 vs. 8.5 months; HR, 0.50; P=0.025), as was progression-free survival (median, 4.2 vs. 3.6 months; HR, 0.56; P=0.013), but there was no significant difference in response rate (7.3% and 9.8%; P>0.05).

These findings support further study of EGFR-targeted agents in RAS wild-type pancreatic cancer.