Panitumumab Research Articles

Acquired gene alteration patterns and post-progression survival: PARADIGM study analysis.

3507 Background: In the phase 3 PARADIGM trial (NCT02394795), adding panitumumab (PAN) to FOLFOX6 improved overall survival (OS) compared with bevacizumab (BEV) in patients (pts) with RASWT mCRC. In this exploratory analysis, we investigated the role of acquired gene alterations in pts who experienced progressive disease (PD) and the impact of these alterations on post-progression survival (PPS). Methods: PPS was defined as the interval from PD to death. Pre- and post-treatment cell-free DNA (cfDNA) was analyzed using the custom PlasmaSELECT-R 91 PGDx panel (NCT02394834). PFS, OS, and PPS were compared by patterns of acquired gene alterations. Results: Among the enrolled 802 pts, 390 discontinued treatment due to PD, of which 276 (70.8%) had evaluable pre- and post-treatment cfDNA samples (PAN, 126; BEV, 150). PAN pts with acquired RTK/RAS alterations had shorter PPS than those without alterations (13.2 vs 18.8 mo, HR 1.88 [95% CI: 1.28–2.76]) with the same trend in OS. BEV pts with acquired CIMP pathway alterations had shorter PPS than those without (14.9 vs 18.6 mo; HR 1.58 [1.09–2.29]); OS had similar results. Co-occurrence of gene alterations was more frequent in PAN vs BEV (overall 52.4% vs 43.3%, RTK/RAS gene co-alterations 25% vs 10%). Co-occurrence of gene alterations resulted in shorter PPS only in PAN pts. Conclusions: Distinctive patterns of acquired gene alterations were observed in PAN- and BEV-treated pts with PD. Co-occurrence of gene alterations, particularly in the RTK/ RAS pathway, was more prevalent with PAN than BEV. Clinical trial information: NCT02394834 .

Abstract 5844: Landscapes of acquired EGFR and VEGF resistance alterations in colorectal cancer: findings from the PARADIGM biomarker study

Abstract Introduction: Resistance mechanisms to anti-epidermal growth factor receptor (EGFR) treatment, such as panitumumab (PAN), in patients (pts) with metastatic colorectal cancer (mCRC) depend on the diversity of acquired gene alterations and clonal variation. To explore resistance mechanisms and emerging genomic alterations during PAN treatment, we analyzed the circulating cell-free DNA (cfDNA) samples from the PARADIGM trial (NCT02394795), which demonstrated survival benefits of PAN over bevacizumab (BEV), an anti-vascular endothelial growth factor (VEGF) antibody, in combination with first-line chemotherapy in pts with RAS wild-type (WT) mCRC. Methods: cfDNA from blood samples were obtained pre- and post-treatment and analyzed for gene alterations using the custom PlasmaSELECT-R 91 PGDx panel (NCT02394834). We analyzed the landscapes of acquired alterations and their association with functional pathways in mCRC according to The Cancer Genome Atlas signaling classification. Result: Among the enrolled 802 pts, 390 discontinued treatment due to progressive disease, of which 276 (70.8%) had evaluable pre- and post-treatment cfDNA samples (PAN, n=126; BEV, n=150). Though the proportion of pts with acquired alterations in any of 30 RTK-RAS-related genes was similar in PAN vs BEV (44.4% vs 42.7%), known EGFR resistance-related genes were observed more frequently in PAN compared with BEV: KRAS (19.1 vs 2.7%), NRAS (9.5 vs 2.7%), BRAF (11.1 vs 0.7%), MAP2K1 (5.6 vs 0.7%), and EGFR (5.6 vs 3.3%). These acquired mutations clustered at hotspots within those genes in the PAN group, unlike in the BEV group. Furthermore, the co-occurrence rates of acquired alterations among the RTK-RAS pathway of the individual cases were higher in PAN (25.4%) vs BEV (9.3%), suggesting an increased subclonal complexity in PAN. There were few acquired alterations predominantly observed in BEV, and their biological significance remains unclear. Conclusion: These results suggest that PAN treatment, compared with BEV, more commonly induces multiple resistant subclones in specific pathways under selective treatment pressure. Our findings provide valuable insight for further investigations into the mechanisms of acquired and resistance associated with PAN and BEV. Citation Format: Katsuya Tsuchihara, Riu Yamashita, Takayuki Yoshino, Kohei Shitara, Jun Watanabe, Hirofumi Yasui, Hisatsugu Ohori, Manabu Shiozawa, Kei Muro, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Ikuo Mori, Masamitsu Hihara, Junpei Soeda, Kouji Yamamoto, Kiwamu Akagi, Atsushi Ochiai, Victor E. Velculescu, Hiroyuki Uetake. Landscapes of acquired EGFR and VEGF resistance alterations in colorectal cancer: findings from the PARADIGM biomarker study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5844.

Abstract 3481: Comparative spatial transcriptomic analysis of monoclonal antibodies targeting the same molecule: A comparison between cetuximab and panitumumab

Abstract Background: In recent years, multiple therapeutic monoclonal antibodies have been developed that target the same molecules. Examples include trastuzumab and pertuzumab for HER2, cetuximab (CTX) and panitumumab (PNT) for EGFR, as well as pembrolizumab and nivolumab for PD-1. Currently, comparative studies between different monoclonal antibodies with same target primarily focus on comparing their efficacy, which makes it challenging to discern the factors contributing to their varied effectiveness. In this study, we conducted a comparative analysis of CTX and PNT using integrated data of fluorescence imaging and spatial transcriptomics (ST) to explore their distribution, as well as the associated cell types and genes in tumor tissues. Method: A FaDu cancer cell line, which has high EGFR expression, was used to establish tumor model in BALB/C nude mice. In the tumor model, fluorescence dye-conjugated CTX or PNT was intravenously administered. In vivo fluorescence imaging was conducted at 0, 2, and 40 hours. Tumor tissues at 2 and 40 hours were dissected for drug distribution images and 10X Visium ST. SPADE algorithm [1], CellDART [2], and Stopover analysis [3] were employed for integrative analysis, cell type deconvolution, and topological association of interesting genes. Results: In vivo imaging demonstrated that both antibodies exhibited high tumor uptake at 2 hrs, with further increase observed at 40 hrs post-injection. Initially, CellDART analysis confirmed that in the 2 hrs sample, both CTX and PNT exhibited a distribution similar to cancer cells among the various cell types. However, in the 40 hrs sample, the distribution pattern resembled that of cancer cells and inflammatory macrophages for both antibodies. A stopover analysis revealed a higher concordance between CTX distribution and EGFR expression in both the 2 and 40 hrs samples compared to that of PNT. Lastly, the top 100 up-regulated differentially expressed genes which are highly associated with drug distribution were identified through SPADE analysis. Notably, when we checked the intersection between CTX and PNT administered samples for these genes, there was 83% discordance in the associated genes in the 2 hrs sample and 93% in the 40 hrs sample. Conclusion: In the examination of the distribution patterns of two distinct therapeutic antibodies targeting EGFR within cancer tissues, a notable observation was made: while the cell types exhibited similarity, the associated genes demonstrated divergence, with different degrees of alignment with the intended target. This analytical approach, scrutinizing the distribution of different antibodies within tissue sharing a common target, holds promise as a widely applicable method for elucidating divergent therapeutic effects.

Abstract 2355: SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies

Abstract SGN-EGFRd2 is an investigational bispecific antibody comprised of two camelid-derived humanized variable heavy chain only (VHH) domains, one targeting Vγ9Vδ2 (gamma delta) T cells and the other targeting the epidermal growth factor receptor (EGFR). Selective antitumor activity occurs when two conditions are met: 1) the molecule engages both EGFR-expressing tumor cells and gamma delta T cells and 2) butyrophilins, in complex with phosphoantigens (pAgs), are expressed by EGFR-positive tumor cells, resulting in gamma delta T cell directed tumor cell killing by activation, degranulation and secretion of cytolytic molecules. The tumor specific proximity of gamma delta T cells and expression of the butyrophilins/pAgs complex results in the killing of EGFR-expressing tumor cells but not EGFR-expressing normal cells. EGFR is an oncogenic receptor tyrosine kinase and target of several classes of therapeutic modalities, including antibodies. Two antibodies are currently approved for the treatment of EGFR-expressing, KRAS wild-type metastatic colorectal cancer (mCRC): cetuximab (CET) and panitumumab (PAN). Although these anti-EGFR therapies provide significant survival benefits to patients, the duration of response is transient, and most patients progress and develop secondary resistance [1]. One such escape mechanism is the acquisition of mutations in the extracellular domain (ECD) of EGFR, which prevent binding of therapeutic antibodies [2]. Because SGN-EGFRd2 will be tested on patients previously exposed to anti-EGFR therapeutic antibodies, it is paramount to assess its binding to EGFR ECD mutations identified in antibody resistant mCRC patients. EGFR-negative A2058 cells were transduced to express wild type EGFR and a panel of EGFR ECD resistance mutations (N=16). The binding specificity and kinetics of SGN-EGFRd2 were compared to CET and PAN by flow cytometry on engineered cell lines and biolayer interferometry, respectively. Results indicated SGN-EGFRd2 maintained the ability to bind to all tested EGFR ECD mutants, whereas CET and PAN were unable to bind several ECD mutants, as previously described [3,4]. SGN-EGFRd2 binding to EGFR ECD mutant cell lines induced the production of interferon gamma and expression of cell surface CD107a on gamma delta T cells, confirming functional engagement. In contrast to current anti-EGFR therapeutic antibodies, SGN-EGFRd2 binding and activity was unaffected by commonly identified EGFR ECD mutations. These findings highlight SGN-EGFRd2 as a novel molecule targeting wild-type EGFR and common EGFR ECD mutations identified in the mCRC setting. Citation Format: Liem Nguyen, Chun-Shu Wong, Serena Wo, Bryan Grogan, Daniel Diolaiti, Maria Corinna Palanca-Wessels, Astrid Clarke. SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2355.

APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p<0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p<0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]

High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of RAS/BRAF mutation status or tumor sidedness.

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S >40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]

90MO Panitumumab (PAN) vs bevacizumab (BEV) in metastatic colorectal cancer (mCRC) by microsatellite stable (MSS), RAS/BRAF, and HER2 amplification (HER2amp) status: Phase III PARADIGM biomarker study

90MO Panitumumab (PAN) vs bevacizumab (BEV) in metastatic colorectal cancer (mCRC) by microsatellite stable (MSS), RAS/BRAF, and HER2 amplification (HER2amp) status: Phase III PARADIGM biomarker study

First-line (1L) panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with HER2 amplification (HER2amp+), RAS wild type (WT) metastatic colorectal cancer (mCRC) according to tumor sidedness.

53 Background: HER2 gene alterations occur in 3%–5% of pts with mCRC and may be associated with aggressive tumor behavior. Gene amplification is a frequent HER2 alteration in mCRC, often leading to HER2 protein overexpression. Preclinical and retrospective studies suggest HER2 alterations may predict anti–epidermal growth factor receptor (EGFR) therapy resistance in mCRC; however, there is limited information regarding the efficacy of 1L anti-EGFR therapy in mCRC pts with HER2 alterations. The PARADIGM trial demonstrated longer median OS with 1L PAN (anti-EGFR) vs BEV (anti–vascular endothelial growth factor), with mFOLFOX6, in RAS WT mCRC (NCT02394795). We evaluated the efficacy of PAN vs BEV in pts with HER2amp + and HER2amp−, RAS WT mCRC from PARADIGM, taking into account primary tumor sidedness. Methods: Baseline plasma ctDNA was obtained from pts with RAS WT mCRC enrolled in PARADIGM; pts with evaluable pretreatment ctDNA were included in the biomarker analysis (NCT02394834). A custom panel (PlasmaSELECT-R 91, PGDx) was used to detect HER2amp+ and HER2amp− samples. OS, PFS, and response rate (RR) were compared in pts with HER2amp+ vs pts with HER2amp−. Results: Of 802 pts with RAS WT mCRC, 733 (91%) had evaluable pretreatment samples; 32 (4%) had HER2amp + (PAN, n=19; BEV, n=13). A lack of a survival benefit with PAN vs BEV was suggested in pts with HER2amp+, regardless of tumor-sidedness (median OS: overall population, PAN, 23.0 mo; BEV, 26.7 mo; HR, 0.96; 95% CI: 0.45–2.04; left-sided population, PAN, 25.1 mo; BEV, 26.7 mo; HR, 0.89; 95% CI: 0.39–2.04]). Data in the right-sided population are not shown for pts with HER2amp+ due to the small sample size. In the overall population, there was a trend toward shorter OS for HER2amp + vs HER2amp− pts (PAN: 23.0 vs 36.3 mo; HR, 1.57; 95% CI: 0.96–2.57; BEV: 26.7 vs 31.6 mo; HR, 1.41; 95% CI: 0.79–2.52). Median PFS and RR were similar between pts with HER2amp + and HER2amp− in PAN or BEV arms (Table). Conclusions: HER2 amplification appears to be prognostic in pts with RAS WT mCRC but may not be predictive of a survival benefit of 1L PAN treatment over BEV. Clinical trial information: NCT02394834 . [Table: see text]

Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial.

LBA1 Background: PARADIGM is the first prospective trial to test the superiority of PAN vs. BEV in combination with standard doublet first-line chemotherapy for patients (pts) with RAS WT mCRC and left-sided primary tumors. Methods: This open-label, multicenter trial in Japan (NCT02394795) randomly selected pts with chemotherapy-naive RAS WT mCRC to PAN + mFOLFOX6 or BEV + mFOLFOX6. Overall survival (OS) as primary endpoint was hierarchically tested in patients with left-sided tumors, followed by those in the full-analysis set (FAS) population. Key secondary endpoints included progression-free survival (PFS), response rate (RR), and curative resection (R0) rate. Results: From May 2015 to June 2017, 823 pts were randomized; 12 did not receive protocol treatment and 9 were excluded due to major deviation of inclusion criteria. A total of 400 pts received PAN and 402 pts received BEV as FAS; 312 and 292 pts had left-sided primary tumors, respectively. OS was analyzed after 448 OS events in left-sided pts with a median follow-up of 61 months. PAN significantly improved OS vs. BEV in both populations: left-sided (HR, 0.82; 95.798% CI, 0.68-0.99, p = .031, which crossed the boundary of significance [0.042]), and FAS (HR, 0.84; 95% CI, 0.72-0.98; p = .030, with < 0.05 as the boundary). Although PFS was comparable between treatment groups, RR and R0 resection rates were higher with PAN compared with BEV (Table). HR for OS in the right-sided population was 1.09. No new safety signal was observed. Conclusions: PAN significantly improved OS vs. BEV in combination with mFOLFOX6 in pts with RAS WT and left-sided mCRC, establishing a standard first-line combination regimen for this population. Clinical trial information: NCT02394795. [Table: see text]

O12-2 Predictive role of tumor location in 1st-line treatment of colorectal cancer: A multicenter retrospective study of JSCCR

Primary tumor location is considered as a predictive factor of first-line targeted therapies of anti-VEGF antibody, bevacizumab (BEV) or anti-EGFR antibody, cetuximab (CET) panitumumab (PAN) in patients with RAS wild-type and metastatic colorectal cancer (mCRC). However, this is based on the post-hoc analyses of clinical trials and there is a lack of real-world evidence. We conducted a multi-center retrospective study to evaluate the efficacy of BEV and CET/PAN according to the primary tumor location.

Activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab or panitumumab in patients with refractory solid tumors.

2522 Background: The phase I GATTO study explored the feasibility, tolerability and preliminary activity of combining Gatipotuzumab (GAT), a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin-1 (TA-MUC1), and an anti-EGFR antibody. Preclinical evidence suggests a complex interaction between TA-MUC1 and EGFR on the cell surface of epithelial tumors and synergistic antibody dependent cell cytotoxicity activity with the double targeting. Methods: Initially 20 patients with refractory metastatic disease were treated with GAT administered at 1400 mg Q2W in combination with the glyco-optimized anti-EGFR antibody Tomuzotuximab (TOM) at 1200 mg Q2W. Due to the risk of infusion related reactions, three cycles of TOM were given before start of combined treatment with GAT. After this regimen was proven safe and no DLT was observed, 30 additional patients including colorectal cancer (CRC) already treated with anti-EGFR antibodies, non-small cell lung cancer (NSCLC), head and neck and breast cancers received TOM and GAT administered at the same doses, with GAT treatment starting already one week after the first dose of the anti-EGFR antibody. As allowed in the study expansion, Panitumumab (PAN) was used in place of TOM in 9 CRC patients at investigator’s choice. Results: By the time of the final analysis in January 2021, 52 patients were enrolled, and 50 received at least one dose of both GAT and anti-EGFR antibodies. Safety was overall good and results are reported in a separate abstract. Because of the difference in treatment schedule, activity results of the two parts of the study are summarized separately. There were 2 and 4 RECIST partial responses in the first and second part of the study, all in CRC patients. In the expansion phase, the median Progression Free Survival (PFS) of CRC patients who received TOM (10) and PAN (9) was 1.9 and 5.5 months, respectively. There were 2 responses in each subgroup and the duration of response was 3.8 and 7.2 months in patients receiving TOM and PAN, respectively. The PFS for NSCLC was 5.3 months and 2 heavily pretreated patients achieved a prolonged control of disease of 10.6 and 9.4 months. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 in serum. In the extension phase patients with baseline values above median appeared to have improved PFS and overall survival; this was not the case for patients of the first part of the study who received GAT only after 3 doses of TOM. Conclusions: Combination of TA-MUC1 and EGFR targeting antibody is safe and feasible. Interesting anti-tumor activity was observed in heavily pretreated CRC and NSCLC patients. Levels of soluble TA-MUC1 may have predictive value and potentially be a companion biomarker for further development of the combination Clinical trial information: NCT03360734.

Safety and tolerability results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab or panitumumab in patients with refractory solid tumors.

2524 Background: The phase I GATTO study explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab (GAT), a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin-1 (TA-MUC1) and an anti-EGFR antibody. Preclinical evidence suggests a complex interaction between TA-MUC1 and EGFR on the cell surface of epithelial tumors driving carcinogenesis processes and synergistic antibody dependent cell cytotoxicity activity with the dual targeting. Methods: Initially the study enrolled in a primary phase (PP) 20 patients with EGFR positive metastatic solid tumors, for whom no standard treatment was available. The first 6 patients were enrolled into a safety run-in phase and the number of dose-limiting toxicities (DLTs) was evaluated, in order to de-escalate the doses if needed. Patients received GAT administered at 1400 mg Q2W in combination with the glyco-optimized anti-EGFR antibody tomuzotuximab (TOM) at 1200 mg Q2W. Due to the risk of infusion related reactions (IRR), the first dose of TOM was reduced to 720 mg split over 2 consecutive days and three cycles of TOM monotherapy were given before start of treatment with GAT. As this regimen was proven safe, no DLT was observed and the initial dose remained unchanged, the study was amended to enroll in an expansion phase (EP) 30 additional patients with refractory colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck and breast cancers. TOM and GAT were given at the same doses and GAT treatment started already one week after the first dose of the anti-EGFR antibody. Additionally investigator had the choice to use a commercial anti-EGFR antibody in place of TOM. Results: By the time of the final analysis in January 2021, 52 refractory patients were enrolled and 50 received at least one dose of both GAT and anti-EGFR antibodies. Panitumumab (PAN) was used in 9 CRC patients. Because of the difference in treatment schedule, results are summarized separately for the 20 and 30 patients in PP and EP. Overall, the combined treatment was well tolerated and no DLT was observed in the whole study, nor related SAE or death. There were no treatment emergent adverse events (TEAEs) leading to dose interruptions or reductions in the PP and 2/30 (6.7%) patients in EP stopped both TOM and GAT. 16 IRRs were reported in 8/20 (40%) PP patients, and 40 IRRs in 10 (33.3%) EP patients. Only one event of chills was severe and only 6 events were related to GAT in the EP, all others to TOM. Other frequent TEAEs were those commonly observed with anti-EGFR treatment such as skin toxicity in 17 (85%) PP and 26 (86.7%) EP patients and hypomagnesemia in 10 (50%) PP and 7 (23.3%) EP patients. Conclusions: Combination of TA-MUC1 and EGFR targeting antibody is safe and feasible. Future studies should test this combination together with chemotherapy Clinical trial information: NCT03360734.

Metastatic colorectal cancer treated with first line chemo and target therapy: nutrition and improved prognosis?

Rationale: Colorectal cancer (CRC) is the most prevalent in Portugal and the first cause of death worldwide. First line treatment for metastatic CRC (mCRC) consists of chemotherapy (CT) combined with target therapy according to molecular analysis; data show that RAS wild type tumours may respond better to CT combined with inhibitor of epidermal growth factor receptor-like Panitumumab (PNb). The role of nutrition in improving treatment efficacy remains unclear, yet low body mass index (BMI) has been associated with worse prognosis and increased CT toxicity. Our goal was to explore the severity of 1st line treatment toxicity, outcomes and the impact of nutrition.

Phase I/II study of panitumumab (PANI) combined with trifluridine/tipiracil (FTD/TPI) in patients (pts) with previously treated RAS wild-type (wt) metastatic colorectal cancer (mCRC): Final results of APOLLON study.

624 Background: Previous preclinical study reported that a combination of PANI with FTD/TPI demonstrated synergistic antitumor activity (Baba, 2017); however, no clinical study has been reported in this combination yet. Therefore, we conducted a phase I/II study to evaluate the efficacy and safety of this combination in pts with RAS wt mCRC. Here, we report the results of final analysis, including follow-up. Methods: Eligible pts had RAS wt mCRC refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, or angiogenesis inhibitors, and had never been treated with anti-EGFR antibodies, FTD/TPI, or regorafenib (REG).Pts received four-week cycles of PANI (every two weeks) and FTD/TPI (twice daily, days 1 to 5 and 8 to 12). The primary endpoint was frequency of dose-limiting toxicity (DLT) in phase I and progression-free survival (PFS) rate at 6 months (M) in phase II. With a PFS rate at 6 M of 48% deemed promising and 29% judged unacceptable, and assuming a one-sided significance level of 5%, the necessary sample size to achieve a power of 80% was estimated to be 47 pts (target sample size, 52 pts). Results: Since no DLT occurred in phase I, the recommended dose was determined to be 6 mg/kg for PANI and 35 mg/m2 for FTD/TPI. In phase II with a median follow-up of 16.5 M, the PFS rate at 6 M (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and overall survival were 5.8 M (95% CI: 4.5–6.5) and 14.1 M (95% CI: 12.2–19.3), respectively. The response rate and disease control rate were 37.0% and 81.4%, respectively. The most common grade 3 or higher adverse events (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), and dermatitis acneiform (9.1%). Subsequent therapy was given to 39 pts (72.2%), including 25 pts (46.3%) treated with REG. Subgroup analyses stratified by age, PS, and primary lesion will be reported at the time of conference presentation. Conclusions: PANI combined with FTD/TPI showed favorable antitumor activity with an acceptable safety profile for previously treated RAS wt mCRC, although the primary endpoint of PFS rate at 6 M did not meet the prespecified threshold. Clinical trial information: NCT02613221.

609TiP - Intermittent or continuous panitumumab (PAN) plus FOLFIRI for first-line treatment of patients (pts) with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC): A randomized phase II trial (IMPROVE)

609TiP - Intermittent or continuous panitumumab (PAN) plus FOLFIRI for first-line treatment of patients (pts) with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC): A randomized phase II trial (IMPROVE)

Synthesis and Characterization of Cetuximab-Docetaxel and Panitumumab-Docetaxel Antibody-Drug Conjugates for EGFR-Overexpressing Cancer Therapy.

The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option.

Abstract P2-09-29: Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes

Abstract Background: Epidermal growth factor receptor (EGFR) is expressed in ˜50% of triple negative breast cancer (TNBC) and has been proposed as a therapeutic target in this disease. However, trials testing EGFR blockade in TNBC failed to show significant clinical benefit. Probable reasons for such results were patient selection based on EGFR expression and the enrollment of heavily pretreated metastatic patients. Our team has conducted two neoadjuvant trials testing the activity of the anti-EGFR antibodies panitumumab (PTB) and cetuximab (CTX) combined with chemotherapy in locally advanced TNBC. Biomarkers predictive of pathological complete response (pCR) were the level of tumor cell EGFR protein expression and tumor-infiltrating lymphocytes' (TILs) profile (PMIDs 24827135, 26649807). The PTB-treated pts had a higher pCR rate (47%) than the CTX-treated pts (24%), but also a twice higher relapse rate, after 5 years of follow-up. Here we report results of genomic and TILs studies, performed in order to reveal possible determinants of recurrences in those trials. Methods: Tumor tissues sampled before and after neoadjuvant therapy (NAT) have been analyzed by next generation sequencing (NGS) using a targeted exome panel (MSK-IMPACT) of 410 cancer-related genes. Gene expression was evaluated by Affymetrix arrays. TIL density was assessed on pre-NAT samples according to Salgado et al, 2014 (PMID 25214542). The correlation between response, recurrences, genomic and TIL findings was analyzed in a case-by-case fashion. Results: Sixteen tumors that achieved pCR (PTB: 11, CTX: 5) and 23 non-pCR tumors (PTB: 11, CTX: 12) have been analyzed. For 14 non-pCR tumors (PTB: 6, CTX: 8) data have been obtained both from the pre-NAT and the post-NAT sample. Among those tumors, 6 recurred within 2 years after surgery (PTMB: 3, CTX: 3) and assays are on-going on several others that relapsed. Several genomic aberrations that potentially played a causative role in opposing to therapy were identified. We observed multiple mutations in the PI3K pathway in several non-pCR or relapsing pts. Interestingly, in a residual tumor (RT) of a non-pCR patient we found 3 different activating mutations in PIK3CA and one in PTEN. Another example of genomic selection induced by pharmacological pressure is the emergence of a HRAS G12S mutation in a RT after CTX. Additional novel findings include in-frame mutations and deletions in ARID1B and PARP1 amplification in non-pCR pts. Most of the tumors which recurred had ≤10% TILs (9/13) and only 4/13 had ≥30%. Among the tumors with a post-NAT RT but without recurrence, 17/33 had ≤10% TILs and 16/33 ≥30%. No particular link between TIL density and mutation pattern was observed. Conclusions: This is an example of a case-by-case approach where we captured the intrinsic inter-tumor heterogeneity, which is likely responsible for the different responses to EGFR-targeting in TNBC. Genes/pathways candidate of resistance to therapy are currently being validated. Citation Format: Radosevic-Robin N, Cocco E, Privat M, Abrial C, Penault-Llorca F, Scaltriti M. Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-29.

Abstract A089: Exploiting clonal evolution and liquid biopsy to overcome resistance to anti-EGFR treatment in metastatic colorectal cancer: the CHRONOS trial

Abstract Background: The EGFR-targeted antibodies cetuximab and panitumumab (MAB-EGFRs) are used for the treatment of RAS-axis wild-type metastatic colorectal cancer (mCRC). Unfortunately, acquired resistance to MAB-EGFRs inevitably develops, dramatically curtailing their clinical use (Misale et al., Cancer Discov 2014). We found that mutations in KRAS, NRAS, and BRAF are the main culprit of this acquired resistance, and that high ctDNA levels of these mutated genes can be found in plasma of progressing patients. However, in preclinical models made resistant to cetuximab, acquired RAS-axis mutated clones decay upon cetuximab withdrawal, allowing tumor cells to regain sensitivity to further anti-EGFR treatment. Paralleling this behavior, RAS-axis WT patients who occasionally benefited from a rechallenge treatment with MAB-EGFRs exhibited corresponding pulsatile levels of mutant RAS ctDNA (Siravegna et al., Nat Med 2015). Collectively, these results suggest that the CRC genome adapts dynamically to intermittent MAB-EGFRs schedules, and provide a molecular rational for rechallenge therapies based on EGFR blockade. Methodology: CHRONOS is a liquid biopsy-driven trial to assess the efficacy of rechallenging with panitumumab (PAN) mCRC patients with ct-DNA-proven RAS-mediated acquired resistance. CHRONOS patients’ selection is based on a progressive enrichment strategy. In the SCREENING phase, multiple wild-type patients [MWTP, i.e., patients not harboring any drivers of resistance to MAB-EGFRs at tumor level (Bertotti et al., Nature 2015)] are identified upfront with a multiplex mCRC-specific tissue-genotyping panel (FUNNEL). In the MOLECULAR phase, MWTP responding to a 1st-line treatment inclusive of MAB-EGFR and developing RAS-mutated ctDNA clones at progression (PD), start 2nd-line chemotherapy and are blood monitored for RAS-related clones' decay. MWTP experiencing a >50% drop in ctDNA RAS levels at 2nd-line PD enter the TRIAL phase and are rechallenged with PAN. The main endpoint is objective response (OR), aiming to achieve a 30% OR rate. 129 MWTP responding and progressing to 1st-line MAB-EGFR-based therapy will be blood-monitored from first to second PD. We expect to find detectable (>3 MAF) ctDNA RAS mutated clones in 80% of cases (N 36), decaying >50% during 2nd-line "EGFR-therapy holiday" (60% of cases). These “ctDNA eligible” patients will receive PAN at 6 mg/kg Q2 weeks until PD or unacceptable toxicity. 27 MWTP will be recruited in TRIAL phase with 6 responses necessary to declare the study positive (β 0.15; α 0.05). Liquid biopsy will be used to correlate the decay kinetics of RAS-extended clone(s) during MAB-EGFR treatment holiday with response to PAN rechallenge, and to link the blood presence of RAS-extended clone(s) during PAN treatment with response and its duration. The tumor ctDNA plasma will be analysed by NGS before and after PAN rechallenge and potential associations identified between different mutated ctDNA clones (RAS or others) and response to PAN rechallenge. Conclusion: This is the 1st trial in mCRC exploiting liquid biopsy and the clonal evolution of tumor cell under treatment pressure, to extend the use of anti-EGFR therapy beyond the point of clinically established resistance in mCRC. (NCT03227926.) Funded by AIRC grant #9970. Citation Format: Salvatore Siena, Alberto Bardelli, Andrea Sartore-Bianchi, Sara Lonardi, Francesco Leone, Francesca Bergamo, Giuseppe Tonini, Filippo De Braud, Filippo Pietrantonio, Lorenza Rimassa, Armando Santoro, Giulia Siravegna, Benedetta Mussolin, Francesco Rua, Erica Francesca Bonazzina, Alessio Amatu, Patrizia Racca, Andrea Ardizzoni, Vittorina Zagonel, Silvia Marsoni. Exploiting clonal evolution and liquid biopsy to overcome resistance to anti-EGFR treatment in metastatic colorectal cancer: the CHRONOS trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A089.

Do We Still Need Phase 2 Trials? Late Obituary for Panitumumab and the SPECTRUM-Trial

Do We Still Need Phase 2 Trials? Late Obituary for Panitumumab and the SPECTRUM-Trial

Interpretation of the updates of NCCN 2017 version 1.0 guideline for colorectal cancer

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.