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2609 Background: It’s been widely recognized that T cells play an essential role in immunotherapy of malignant tumors. Notably, in our previous PRaG trial, we observed that T cell decreasing occurred in some patients with advanced refractory solid tumors during PD-1 inhibitor combined with stereotactic body radiation therapy (SBRT) / hypo-fractionated radiotherapy (HFRT) and granulocyte macrophage-colony stimulating factor (GM-CSF) treatment which might be one of the reasons for their poor efficacy. To further improve the efficacy of immunotherapy combined with radiotherapy, we optimized the PRaG regimen and added interleukin-2 (IL-2), which amplifies and activates T cells. We conducted PRaG 2.0 trial to further explore the effect of T cells on efficacy. Methods: Patients with advanced refractory solid tumors who lacked or were intolerant to the available standard of care were enrolled to receive PRaG 2.0 regimen. A treatment cycle consisted of SBRT or HFRT (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days (d1-7), and then sequentially followed by IL-2 2million IU SC once daily for 7 days(d8-14). PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). This trial was registered at www.clinicaltrials.gov with identifier number NCT04892498. Results: With the cutoff date of 31 December 2021, a total of 34 patients were enrolled, in which 28 patients (82%) completed at least 1 tumor assessment with a median follow-up time of 5.5 months (95%CI: 4.4, 6.6). Median PFS and overall survival (OS) were currently not reached. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 71.4% by RECIST1.1. Compared to baseline, no significant decrease of T cells, including CD3+, CD4+, and CD8+ T cells, have been observed in 19 patients who completed ≥ 4 treatment cycles. Treatment-related adverse events (TRAE) occurred in 28 of 34 (82.4%) patients, Grade ≥ 3 TRAEs occurred in three patients (8.8%). TRAEs leading to treatment interruption occurred in three patients (8.8%). Conclusions: These preliminary results of PRaG 2.0 trial demonstrate that PD-1 inhibitors in combination with radiotherapy, GM-CSF, and IL-2 could potentially maintain the T cells and improve clinical outcomes in patients with advanced refractory solid tumors with acceptable toxicity. Clinical trial information: NCT04892498.

e15561 Background: Immunotherapy has improved outcomes for metastatic colorectal cancer(mCRC) patients with MSI-H/dMMR but has not been effective in MSS/pMMR tumors, which comprise 95% of mCRC. In metastatic cancers, radiotherapy can be used as a local therapy and a sensitizer to PD-1/PD-L1 inhibitors. The synergistic effects of radiotherapy and PD-1/PD-L1 inhibitors can be reinforced by adding cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2(IL-2). Our previous PRaG trial demonstrated that PD-1 inhibitors in combination with radiotherapy and GM-CSF could improve clinical response in patients with advanced refractory solid tumors. We found that mCRC patients with MSS/pMMR could also benefit from the PRaG regimen. Methods: Patients of mCRC with MSS/pMMR were collected from the PRaG trial and PRaG 2.0 trial. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 14 days(d1-14), or GM-CSF 200μg (d1-7), and then sequentially followed by IL-2 200 million IU SC once daily for 7 days(d8-14). PRaG regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose. Pooled analysis of response rate (ORR), median progression-free survival (PFS), and treatment-related adverse eventswere calculated. Results: With the cutoff date of 31 December 2021, a total of 9 mCRC patients with MSS/pMMR were enrolled. All of the patients completed at least 2 cycles of PRaG therapy and one evaluation. The median follow-up was 7.6 months (95%CI, 3.8, 11.4). The ORR was 22.2%, and the disease control rate(DCR) was 66.7%. The median PFS was 5.6 months (95%CI, 1.5 to 9.7). One patient got complete remission, with PFS over 17months. Treatment-related adverse events (TRAE) occurred in 7 of 9 (77.8%) patients. One patient (11.1%) occurred Grade3 TRAE of renal insufficiency. Conclusions: Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity.

e14565 Background: The development of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy with the advance of molecular and tumor microenvironment. Radiotherapy produces an immunomodulatory effect that may act synergistically with PD-1/PD-L1 inhibitor in multiple malignancies. Previous phase II trial showed HFRT/SBRT combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results(Yuehong Kong et al. ASTRO 2021). RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumours. RC48-ADC combined with HFRT, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 (PRaG3.0 regimen) could further improve the synergistic antitumor effects, this precise combination therapy paradigm provides an exploratory path for the treatment of pan-cancer. An exploratory phase II, open-label, multi-centre, single-arm study was conducted to evaluate the initial clinical efficacy and safety of PRaG3.0 regimen for treatment of HER2-expressing advanced solid tumors. Methods: Participants with advanced, confirmed HER2-expressing(IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC(2.0 mg/kg d1, every 3 weeks), then HFRT (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF(200 μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of HFRT. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT05115500. Results: With the cutoff date of 11 February 2022, a total of 8 patients were enrolled. Among 6 patients who had at least one tumor assessment, involved gastric cancer(3/6), breast cancer(1/6), cervical cancer(1/6), pancreatic cancer(1/6). The ORR was 66.7% (4/6) and disease control rate (DCR) was 83.3%(5/6). One cervical cancer and one pancreatic cancer achieved complete remission. The most common treatment-related adverse events (TRAEs) were alopecia (37.5%), fatigue (25%) and hepatic damage(12.5%). No Grade 3 and higher adverse events occurred. Conclusions: The PRaG3.0 regimen manifested manageable safety profile and encouraging efficacy. So PRaG3.0 regimen is considered as a promising salvage treatment for patients with HER2-expressing advanced solid tumors. And the conclusion should be validated in more patients subsequently. Clinical trial information: NCT05115500.

Background Nearly 50% of new gastric cancer cases and gastric cancer-related deaths worldwide occur in China. No global consensus has been reached about the optimal management of locally advanced gastric cancer. Although the Guidelines for the Diagnosis and Treatment of Gastric Cancer from the National Health Commission of China, which has been updated three times since 2010, explicitly emphasize the necessity of adjuvant chemoradiation, few clinical institutions in China routinely adhere to the recommended radiotherapy guidelines. This study aimed to examine the efficacy, in terms of locoregional control and long-term survival, and the safety of adjuvant radiotherapy using intensity-modulated radiation therapy (IMRT) with concurrent and adjuvant fluoropyrimidine-based chemotherapy for gastric cancer. Methods This was a retrospective evaluation of 156 patients with high-risk gastric cancer who underwent adjuvant chemoradiotherapy between September 2008 and May 2019. The prescribed planning target volume median dose was 45 Gy in 1.8 Gy daily fractions, and all patients received concurrent and adjuvant fluoropyrimidine-based chemotherapy. Locoregional control, distant metastasis, and overall survival rates were estimated. Clinicopathological characteristics and patterns of failure were retrospectively reviewed to identify factors associated with survival and recurrence. Results The median follow-up duration was 56 months (range 3–130 months) for all patients. Of the patients, 11 (7.1%) were lost to follow-up, and 49 (31.4%) and 104 (66.7%) had stage II or III disease according to the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging criteria. The frequencies of acute grade 3 or 4 gastrointestinal and hematological toxicity were 9.6% and 10.9%, respectively. In total, 152 patients (97.4%) completed the entire chemoradiation regimen. No toxicity-related deaths occurred. Nineteen patients (12.2%) had locoregional recurrence, 26 (16.7%) had distant metastases, and 12 (7.7%) had peritoneal metastasis. The overall survival (OS) rates were 83.5%, 65.0%, and 59.5%, while the disease-free survival rates were 75.1%, 61.0%, and 55.6% at 1, 3, and 5 years, respectively. In the multivariate analysis, age, pathological T stage and lymph node ratio (LNR) were found to be independent predictors of OS. Conclusion Postoperative concomitant IMRT and chemotherapy were well tolerated, with acceptable toxicities and encouraging locoregional tumor control and long-term survival. The LNR can be used as an important prognostic indicator for OS. Adjuvant chemoradiotherapy should be considered for all patients with a high risk of locoregional recurrence, especially in China.

Purpose/Objective(s) Advanced cancer patients refractory to chemotherapy have a poor prognosis and few therapeutic options. Evidences have shown that radiotherapy can induce a systemic anti-tumor immune response, which may potentially sensitize PD-1 inhibitors. Immunomodulatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) may have a synergistic effect with radiotherapy or anti-PD-1 therapy. A phase Ⅱ trial was conducted to assess the clinical efficacy and safety of stereotactic body radiation therapy (SBRT) or hypofractionated radiotherapy (HFRT) combined with PD-1 inhibitor and GM-CSF (PRaG regimen) for the treatment of chemo-refractory solid tumor patients. Materials/Methods Subjects with multi-metastatic solid tumors and progressed beyond at least first-line chemotherapy were enrolled. In a PRaG cycle, SBRT or HFRT (3 × 8 Gy or 3 × 5 Gy) was delivered for one metastatic site, GM-CSF 200 µg was subcutaneously injected daily for 2 weeks after radiotherapy, and sindilimab 200 mg or toripalimab 240 mg was intravenously administered once within one week after completion of SBRT or HFRT. PRaG was repeated every 21 days for at least 2 cycles. After discontinuation of PRaG and patient had no disease progression, sindilimab or toripalimab monotherapy was given until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS). This trial is registered in chictr.org.cn (No. ChiCTR 1900020175). Results By February 2021, a total of 48 patients were enrolled. Forty-three patients (89.6%) completed at least two cycles of the triple-combination therapy, and the remaining five patients received one cycle of the triple therapy and continued treatment. Treatment-related adverse events (TRAE)of any grade occurred in 35 (72.9%) patients. The common adverse events were fatigue 52.1%, anorexia 47.9%, thyroid dysfunction 29.2%, liver dysfunction 18.8% and rash 14.6%. Two patients (4.2%) experienced Gr3 and higher TRAE. Both patients had lung lesions irradiated during PRaG and one patient experienced Gr3 pneumonia and another patient experienced Gr4 pneumonitis. Forty-one patients completed at least one efficacy evaluation, seven patients had confirmed partial response (PR), and the objective response rate (ORR) was 14.6% (RECIST 1.1). The median PFS was 5.2 months (95% CI, 4.3-6.1). Conclusion The PRaG regimen is well tolerated with acceptable toxicity. Our data suggest that SBRT or HFRT can sensitize the anti-tumor effects of anti-PD-1 therapy and produce a great synergistic efficacy. The PRaG regimen could contribute to a promising salvage treatment for patients with chemotherapy-refractory metastatic solid tumor.

e15173 Background: Patients with refractory metastatic solid tumors have poor prognoses and few therapeutic options. The application of PD-1 inhibitor has led to a paradigm shift in the treatment of advanced cancer, but its efficacy as a monotherapy is limited. Previous evidence has shown that the anti-tumor effects might be reinforced when PD-1 inhibitor combines with radiotherapy or granulocyte macrophage-colony stimulating factor (GM-CSF). An exploratory study was conducted to assess the clinical efficacy and safety of PD-1 inhibitor combined with radiotherapy and GM-CSF (PRaG regimen) for the treatment of refractory patients. Methods: Participants had multimetastatic solid tumors progressing beyond at least first-line chemotherapy.They were treated with hyperfractionated radiotherapy (3 doses of 8Gy or 5 doses of 5Gy) for each metastatic site. On the second day after radiotherapy, PD-1 inhibitor 200 mg once was intravenously administered and GM-CSF 200 µg daily was subcutaneously injected for 2 weeks. This course was repeated every 3 weeks, targeting a second metastatic site. Triple-combination therapy. (PRaG regimen) was given for at least 2 cycles. After combination therapy, maintenance with PD-1 inhibitor was administered until disease progression or unacceptable toxicity. The main outcome measures included safety, toxicity, progression-free survival (PFS) and objective response rate (ORR) after three cycles of treatment. Results: A total of 16 patients were enrolled.The median number of metastatic lesions was 7.5(95%CI, 5.3 to 19.5) and the median sum of the longest diameter of all measurable lesions was 161.7mm (95%CI, 104.1 to 279.3mm).All patients completed two cycles or more of triple-combination therapy. The ORR was 20% and the median PFS was 3.3 months (95%CI, 2.3to 7.2months) at the time of evaluation. Treatment-related adverse events of any grade occurred in 13 (81%) patients, and grade 3 and higher adverse event like pneumonitis occurred in 2 (11.0%) patients. Conclusions: The PRaG regimen is well tolerated with acceptable toxicity. For patients with resistant metastatic solid tumors, low efficacy and high cytotoxicity are commonly observed in conventional therapy. With the new chemo-free PRaG regimen, myelosuppression was not observed and gastrointestinal side effects remained low. So, PRaG regimen is considered as a promising salvage treatment for patients with chemotherapy-refractory metastatic solid tumor. The suggested mechanism might involve radiosensitization of immunotherapy. Clinical trial information: ChiCTR1900020175 .