SOLARIS (Alliance A021703): A Multicenter Double-blind Phase III Randomized Clinical Trial (RCT) of Vitamin D (VitD) Combined with Standard Chemotherapy Plus Bevacizumab (bev) in Patients (pts) with Previously Untreated Metastatic Colorectal Cancer (mCRC).

Background

• Higher 25-hydroxyvitamin D levels are associated with improved CRC survival. 

• The SUNSHINE phase II RCT found that pts with mCRC receiving 1st-line chemo + bev + high-dose VitD3 had improved progression-free survival (PFS) vs standard-dose VitD3. 

Aim

• SOLARIS was designed to further evaluate the efficacy of VitD in mCRC.

Methods

• Double-blind phase III RCT. 

• Eligible pts had mCRC and no prior therapy; ECOG PS 0-1; and were not taking VitD ≥2,000 IU/d. 

• Pts received mFOLFOX6 or FOLFIRI + bev with 1:1 randomization to high-dose VitD3 (8,000 IU/d x 14d then 4,000 IU/d) vs standard-dose (400 IU/d). 

• Stratification factors: chemo backbone, PS, tumor sidedness. 

• Pts were treated until disease progression, unacceptable toxicity, or withdrawal of consent. 

• The primary intent-to-treat analysis compared PFS between arms. A total of 273 PFS events from 450 pts with 1 interim analysis for futility yields 90% power to detect HR 0.70 (mPFS 10 vs 14.3 mo) using a 1-sided log-rank test with α=0.05. 

• Secondary endpoints: response rate (RR), overall survival (OS), toxicity.

Results

• N= 455 pts

• Median age - 59 yrs (range 27-92)

• Male - 60%

• PS 0 - 52%

• Left-sided primary - 64%

• Median follow-up for PFS - 20 mo (Q1, Q3: 7, 35 mo) with 286 events

• High-dose VitD3 did not improve PFS vs standard-dose VitD3 (mPFS 11.8 vs 10.3 mo; HR 0.92, 95% CI 0.73-1.16; log-rank P=0.25)

• RR - 51% vs 44% (P=0.12)

• mOS - 25.6 vs 27.0 mo (HR 1.05, 95% CI 0.81-1.36; log-rank P=0.34)

• Pre-planned subgroup analyses show a PFS benefit in pts with left-sided mCRC treated with high- vs standard-dose VitD3 (HR 0.74, 95% CI 0.55-1.00; P interaction=0.02). 

• The most common grade ≥3 toxicities were not different between arms, including neutropenia/leukopenia, hypertension, peripheral neuropathy, and diarrhea.

Conclusions

Addition of high-dose VitD3 to standard treatment did not improve PFS vs standard-dose VitD3 in pts with mCRC, although a potential benefit was seen in pts with left-sided mCRC.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Neoadjuvant Immunotherapy in Locally Advanced MMR-deficient Colon Cancer: 3-year Disease-free Survival from NICHE-2

Background

• Patients with MMR-deficient (dMMR) colon cancer have limited benefit from standard-of-care chemotherapy, with recurrence rates of up to 40% in stage 3 disease. 

• In NICHE-2, we previously showed a 99% pathologic response rate, including 95% major pathologic responses (MPR) and 68% pathologic complete responses (pCR). 

Aim

To present the previously unreported primary endpoint of 3-year disease-free survival (DFS).

Methods

• Patients with locally advanced dMMR colon cancer received ipilimumab on Day 1 and nivolumab on Day 1+15, followed by surgery within 6 weeks. 

• The study had two independent primary endpoints: safety and 3-year DFS. 

• As reported previously, the safety endpoint was met. 

• For DFS, a 3-year DFS rate of 93% would be deemed successful, at a power of 80% and a 2-sided alpha of 2.5%, assuming an 82% 3-year DFS in historical controls. 

• Circulating tumor DNA (ctDNA) was analyzed using the SignateraTM tumor-informed assay on plasma samples from baseline, Day 15, pre-surgery and 3 weeks post-surgery (minimal residual disease (MRD)) timepoints.

Results

• Of the 111 patients in the efficacy analysis, 64% had cT4 tumors. 

• With a median follow-up after surgery of 36.5 months (range 7.8 – 83.4), all patients were alive and there were no disease recurrences, resulting in a 3-year DFS of 100%. 

• In 108 patients with available plasma samples, baseline ctDNA was detected in 92%. 

• On Day 15, 45% of these patients had cleared ctDNA. 

• While not different at baseline, ctDNA levels on Day 15 and pre-surgery were significantly lower in pCR vs MPR groups. 

• Pre-surgery ctDNA clearance was observed in 94% of patients with a pCR and 70% with an MPR. 

• 16 patients remained ctDNA+ pre-surgery, albeit with significant reductions in ctDNA levels, and included 2 of 3 partial responders and 1 of 1 non-responder. 

• All patients were ctDNA negative at the MRD timepoint.

Conclusion

Here we show a 100% 3-year DFS in patients with dMMR colon cancer treated with one dose of ipilimumab and two doses of nivolumab prior to surgery. The survival data are also supported by negative ctDNA at the MRD timepoint in all patients, while on-treatment ctDNA dynamics provide an additional monitoring instrument for future trials on organ preservation.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.

Efficacy and Safety of Ponsegromab, A First-in-class, Monoclonal Antibody Inhibitor of Growth Differentiation Factor 15, in Patients with Cancer Cachexia: A Randomized, Placebo-controlled, Phase II Study. 

Background

Ponsegromab is a humanized monoclonal antibody targeting growth differentiation factor 15 (GDF-15), a circulating cytokine implicated in cachexia. 

Aim

To report the results of a phase 2, randomized, double-blind trial of ponsegromab vs placebo in patients with cancer cachexia.

Methods

• Patients with cancer cachexia and elevated serum GDF-15 (≥1500 pg/mL) were randomized 1:1:1:1 to subcutaneous ponsegromab (100, 200, 400 mg) or matching placebo every 4 weeks for 12 weeks. 

• Primary endpoint - Change in weight from baseline to 12 weeks. 

• Other endpoints - Change in appetite and cachexia symptoms (Anorexia Cachexia Subscale and 5-item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia 

Results

Endpoint	Placebo-adjusted change from baseline at Week 12 in Ponsegromab 400 mg dose group	1-sided p value
Primary endpoint, median (90% credible interval)
Weight increase, kg	3.00 (1.68, 4.34)	-
Other endpoints, LS mean (90% confidence interval)
FAACT- Anorexia Cachexia Subscale*	4.11 (1.06, 7.17)	0.01
FAACT- 5-item Anorexia Symptom Score†	2.30 (0.68, 3.92)	0.01
Non-sedentary physical activity, min/day	49.85 (10.62, 89.08)	0.02
Total vector magnitude, activity counts/100 per day	2203.18 (84.51, 4321.85)	0.04
LSMI, cm2/m2	2.15 (0.63, 3.66)	0.01

• N= 187 patients (39.6% NSCLC, 31.6% pancreatic, & 28.9% CRC; 73.3% stage 4) were randomized. 

• Ponsegromab resulted in significant dose-responsive increases in weight, with placebo-adjusted modeled median (90% credible interval) increases of 1.33 kg (0.49, 2.34) [100 mg], 2.08 kg (1.08, 3.15) [200 mg] and 3.00 kg (1.68, 4.34) [400 mg] at 12 weeks. 

• Placebo-adjusted weight gain was observed from week 4 in all ponsegromab groups. 

• Improvements across symptoms, overall activity, and LSMI were observed in the 400 mg group relative to placebo. 

• All-causality and treatment-related adverse events occurred in 70.4% and 7.7% of ponsegromab-treated patients and 80.0% and 8.9% of placebo-treated patients, respectively.

 

*Scale ranges from 0 to 48 (higher scores indicate a better outcome). †Scale ranges from 0 to 20 (higher scores indicate a better outcome). 

 

Conclusion

Ponsegromab improved weight, symptoms, overall activity, and skeletal muscle mass in patients with cancer cachexia and elevated GDF-15, confirming GDF-15 as a primary driver of cancer cachexia.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.

Preoperative Modified FOLFIRINOX (mFOLFIRINOX) With or Without Chemoradiation (CRT) in Borderline Resectable Pancreatic Cancer (BRPC): Results from the Randomized Phase II Trial PANDAS/PRODIGE 44

Background

• The role and the safety of CRT following mFOLFIRINOX administration in BRPC is unknown. 

Aim

To understand role and the safety of CRT following mFOLFIRINOX administration in BRPC. 

Methods

• Patients (pts) with ECOG PS 0/1 and BRPC defined according to centrally-reviewed radiographic NCCN criteria received neoadjuvant mFOLFIRINOX for 4 cycles. 

• Those who had tumour controlled at restaging were randomized between two additional cycles of mFOLFIRINOX (arm A) alone or followed by a CRT (50.4 Gy in 28 fractions with capecitabine 825mg/m2 BID 5 days a week) prior to surgery. 

• Patients without disease progression then underwent a pancreatectomy and adjuvant chemotherapy for 3 months (gemcitabine or 5-FU/folinic acid before 6/2008, mFOLFIRINOX thereafter). 

• Primary endpoint - R0 resection (ITT analysis). 

• Secondary endpoints - overall survival (OS), locoregional relapse-free survival, metastasis-free survival and toxicity.

Results

• N= 248 patients who were assessed for eligibility, 139 patients had a BRPC according to external radiographic review. 

• 130 patients were enrolled and 110 patients were finally randomized (54 pts arm A; 56 pts arm B). 

• Median age - A: 66y, B: 61y

• Median CA 19-9 level - A: 65 U/ml, B: 169 U/ml

• ECOG PS - A: 62% PS 0, B: 52% PS 0

• 30 pts did not have a pancreatic resection due to tumor progression (7 pts arm A; 13 pts arm B), unresectable disease (1 pt arm A), physician or pt decision (4 pts arm A, 1 pt arm B), adverse event (1 in each arm), COVID-19 infection (1 pt arm A), or death (1 pt arm B). 

• 37 pts (69%) in arm A and 31 pts (55%) in arm B had tumor resection. 

• R0 resection was achieved in 20/37 pts (54.1%) in arm A and 18/31 pts (58.1%) in arm B. 

• ypCR was observed in 3 pts (8.1%) in arm A and 9 (29%) in arm B. 

• mOS - 32.8 months (95%CI: 22.7 – 55.4) in arm A and 30 months (95%CI: 16.5 – nr) in arm B. 

• Among pts who underwent pancreatectomy, the median OS was 35.7 months (95%CI: 22.2 – 55.4) and 47.9 months (95%CI: 23.3 – nr) in arm A and B, respectively.

Conclusion

Neoadjuvant mFOLFIRINOX was associated with favorable OS but mFOLFIRINOX with conventional CRT did not improve R0 nor OS compared to mFOLFIRINOX without preoperative CRT in patients with BRPC.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.

Phase III Study of SHR-1701 versus Placebo in Combination with Chemo as First-line (1L) Therapy for HER2-negative Gastric/Gastroesophageal Junction Adenocarcinoma (G/GEJA)

Background

• SHR-1701 is a bifunctional agent composed of an IgG4 mAb targeting PD-L1 fused with extracellular domain of the TGF-βIIR.

Aim

To assess the addition of SHR-1701 to standard chemo in patients (pts) with previously untreated, unresectable locally advanced or metastatic HER2-negative G/GEJA. 

Methods

• This was a 2-part phase 3 study.

• In part 1, the recommended dose of SHR-1701 was determined to be 30 mg/kg, when combined with CAPOX. 

• In the multicenter, randomized, double-blind, part 2, pts were randomized (1:1) to receive SHR-1701 (30 mg/kg, iv, q3w) or matching placebo, plus CAPOX. 

• Randomization was stratified by PD-L1 CPS (≥5 vs <5), ECOG PS (0 vs 1), and peritoneal metastasis (yes vs no). 

• Primary endpoint - OS, assessed in population with PD-L1 CPS ≥5 and in ITT population.

Results

• From Mar 11, 2022 to Jan 13, 2024, 731 pts were randomly assigned to SHR-1701+chemo (N=365) or placebo+chemo (N=366). 

• As of May 20, 2024, median follow-up was 8.5 mo (IQR 5.6–13.2).

• mOS in pts with PD-L1 CPS ≥5 - Significantly prolonged with SHR-1701+chemo vs placebo+chemo (16.8 vs 10.4 mo; HR, 0.53 [95% CI 0.40–0.68]; p<0.0001)

• OS in the ITT population – 15.8 vs 11.2 (HR 0.66; 0.53-0.81; p<0.0001

Conclusion

1L SHR-1701 plus CAPOX showed a statistically significant and clinically meaningful benefit in OS compared with placebo plus CAPOX in pts with HER2-negative G/GEJA, both in PD-L1 CPS ≥5 population and in overall population regardless of PD-L1 level, presenting as a new treatment option.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.

The Randomized Phase III Study of Bi-weekly Trifluridine/Tipiracil (FTD/TPI) plus Bevacizumab (BEV) vs. FTD/TPI Monotherapy for Chemorefractory Metastatic Colorectal Cancer (mCRC): 1-year Follow-up Updated Data from JCOG2014 (ROBiTS)

Background

• Based on the SUNLIGHT trial, FTD/TPI plus BEV combination has been regarded as standard therapy in the late-line treatment for patients with mCRC. 

• However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. 

• JCOG2014 is a phase III trial to confirm the superiority of bi-weekly (1 week-on, 1 week-off) FTD/TPI plus BEV combination over 4-week intervals (2 weeks-on, 2 weeks-off) FTD/TPI monotherapy. 

• An initial report was presented at ASCO-GI 2024. 

Aim

To present survival outcomes with adequate observation.

Methods

• Patients who were refractory or intolerant to standard chemotherapy for the treatment of mCRC were randomly assigned, in a 1:1 ratio to receive 4-week intervals FTD/TPI 70 mg/m2/day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5 mg/kg (arm B).

• Primary endpoint - overall survival (OS)

• Secondary endpoints - progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety.

Results

• This study was terminated early based on the SUNLIGHT trial. 

• Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). 

• Baseline characteristics were well balanced. 

• Median follow-up - 16.9 months 

• mOS - 13.0 vs. 10.6 months (HR, 0.919; 95% confidence interval [CI], 0.617 to 1.369) 

• mPFS - 2.4 vs. 4.0 months (HR, 0.544; 95% CI, 0.387 to 0.763). 

• RR - 1.3% vs. 5.3% 

• DCR - 45.3% vs. 53.3%. 

• The most common Grade 3 or higher adverse events in each arm were neutropenia (46.6% vs. 23.7%), anemia (15.1% vs. 3.9%), fatigue (2.7% vs. 7.9%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%), hypertension (4.1% vs. 3.9%) and febrile neutropenia (4.1% vs. 0%).

Conclusions

Bi-weekly FTD/TPI plus BEV combination in late-line mCRC extends PFS and reduces hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy, though no survival benefit was observed.

Reference

Annals of Oncology (2024) 35 (suppl_2): S428-S481. 10.1016/annonc/annonc1588

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)

Background

• Inoperable locally recurrent/metastatic SCAC is associated with suboptimal PFS and OS, despite high initial response rates to platinum-based chemo. 

• Retifanlimab, an anti–programmed cell death (PD)-1 monoclonal antibody, has shown antitumour activity in pts with advanced SCAC who progressed on platinum-based chemo (Rao S. ESMO Open. 2022;7:100529). 

Aim

• To evaluate the addition of retifanlimab to standard-of-care (SoC) chemo for previously untreated locally recurrent/metastatic SCAC.

Methods

• This phase 3, double-blind, controlled trial enrolled treatment-naive pts aged ≥18 y with inoperable, locally recurrent/metastatic SCAC; (neo)adjuvant/radiosensitising chemo and well-controlled HIV infection were permitted. 

• Pts were randomised 1:1 to 6 cycles of standard-dose C-P plus placebo (P arm) or retifanlimab 500 mg q4w (R arm) for up to 1 y with possibility of crossover. 

• Primary endpoint - PFS by blinded independent central review per RECIST v1.1

• Secondary endpoints - OS (key endpoint), ORR, DCR, DOR, safety, and PK.

Results

• As of 15 April 2024, 308 pts (R arm, 154; P arm, 154) were enrolled; 

• Median (range) age - 62 (29, 86) y

• Female - 72% 

•  White - 87% 

• Known HIV-positive - 4% 

• Liver metastases - 36%

• The trial met its primary endpoint

•  mPFS was significantly higher in the R vs P arm (9.30 vs 7.39 mo; HR [95%CI], 0.63 [0.47, 0.84]; P=0.0006)

• A strong trend of improved OS was seen despite immature data (Table). 

• Overall, addition of retifanlimab was tolerable, with no new safety signals to compromise or disrupt chemo administration. 

Efficacy by blinded independent central review of retifanlimab plusC-P vs placebo plus C-P in pts with SCAC

Variable	Retifanlimab + C-P (n=154)	Placebo + C-P (n=154)	P Value HR (95% CI)
Median PFS, mo (95% CI)	9.3 (7.5, 11.3)	7.4 (7.1, 7.7)	P=0.0006 HR=0.63 (0.47, 0.84)
Median PFS follow-up time, mo (range)	7.6 (0.0, 33.9)	7.1 (0.0, 27.4)	–
Median OS, mo (95% CI)	29.2 (24.2, NE)	23.0 (15.1, 27.9)	P=0.0273 HR=0.70 (0.49, 1.01)
Median OS follow-up time, mo (range)	14.8 (0.6, 38.3)	12.9 (0.0, 40.4)	–
ORR, % (95% CI)	55.8 (47.6, 63.8)	44.2 (36.2, 52.4)	P=0.0129*
DCR, % (95% CI)	87.0 (80.7, 91.9)	79.9 (72.7, 85.9)	–

*Nominal P value.

Conclusions

This international study demonstrates encouraging efficacy and favourable benefit/risk ratio for retifanlimab plus SoC chemo as first-line treatment of locally recurrent/metastatic SCAC and suggests a new SoC.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623