Tag: Rectal Cancer

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

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SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

Sotorasib (LUMAKRAS®) is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

CodeBreaK 300 trial is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively. Overall survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960-mg dose appeared to yield more clinically significant benefits than the 240-mg dose, across all efficacy endpoints, without additional toxic effects. Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

FDA Approves Fruquintinib in Refractory Metastatic Colorectal Cancer

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SUMMARY: The FDA on November 8, 2023, approved Fruquintinib (FRUZAQLA®) for adult patients with metastatic Colorectal Cancer (mCRC) who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). Regorafenib has limited efficacy and its adverse effects, particularly hepatotoxicity and fatigue, may be difficult to manage. Treatment options are limited for those who progress on these therapies and there is therefore a strong unmet clinical need.

The VEGF pathway plays a very important role in the neoangiogenesis associated with tumor proliferation. Antiangiogenic agents targeting the VEGF pathway inhibit new blood vessel growth and lead to vascular regression, tumor vessel normalization and constriction, in addition to offsetting the ability of chemotherapy to induce VEGF. This benefit was noted in the SUNLIGHT trial which demonstrated longer Overall Survival and Progression Free Survival among patients with refractory metastatic CRC, treated with LONSURF® plus Bevacizumab, compared to LONSURF® alone (N Engl J Med 2023; 388:1657-1667).

Fruquintinib is a highly selective and potent, oral small molecule inhibitor of VEGFR1/2/3. Fruquintinib was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for the potential use as part of combination therapy.

The present FDA approved was based on two Phase III trials, FRESCO and FRESCO-2. FRESCO is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial conducted in China to evaluate the efficacy and safety of oral Fruquintinib, as third-line or later therapy in patients with metastatic CRC. It should be noted that unlike treatment patterns in North America and Europe, VEGF inhibitors such as Bevacizumab and Aflibercept are not routinely integrated into first- or second-line therapy in China. In this study 416 eligible patients (N=416) who had tumor progression following treatment regimens that included Fluoropyrimidine, Oxaliplatin, and Irinotecan were randomly assigned to receive Fruquintinib 5 mg (N=278) or placebo (N=138), both in combination with best supportive care, given orally once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression or intolerable toxicity. Randomization was stratified by prior use of VEGF inhibitor treatment (yes versus no) and K-ras mutational status (wild type versus mutated). The mean age was 55 years and most baseline demographics, disease characteristics, and prior treatments were similar between the treatment groups. Over 65% of patients had liver metastases. The Primary end point was Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate, Duration of Response and Safety.

The median Overall Survival was significantly prolonged with Fruquintinib compared with placebo (9.3 months versus 6.6 months; HR for death=0.65; P<0.001). The median PFS was also significantly increased with Fruquintinib (3.7 months versus 1.8 months; HR for progression or death=0.26; P<0.001).

The FRESCO-2 study is a global, multi-regional, randomized, placebo-controlled, Phase III trial conducted separately in the U.S., Europe, Japan and Australia among patients with heavily pretreated metastatic colorectal cancer. The reason for this trial was that practice patterns are different in these countries compared to China, with VEGF inhibitors such as Bevacizumab routinely integrated into first- or second-line therapy in these countries. In this study, 691 eligible patients (N=691) were randomly assigned (2:1) to receive Fruquintinib 5 mg (N=461) or matched placebo (N=230) orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Patients received therapy until disease progression or unacceptable toxicity. This study included histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to LONSURF® or Regorafenib, or both. Patients had received a median of 4 lines of previous systemic therapy for metastatic disease, and 73% of the eligible patients had received more than 3 lines of therapy for metastatic disease. Patients were stratified based on previous therapy with LONSURF® or Regorafenib, or both, RAS mutation status, and duration of metastatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Duration of Response.

This study met its Primary endpoint and the median OS was 7.4 months in the Fruquintinib group versus 4.8 months in the placebo group (HR=0.66; P<0.0001). This represented a 34% reduction in the risk of death in the Fruquintinib group. The median PFS in the Fruquintinib group was 3.7 months which was also statistically significant. The median Duration of Response was 10.7 months, the Disease Control Rate was 56%, and 41% of patients were alive at 9 months. The most common Grade 3 or worse adverse events in the Fruquintinib group included hypertension (14%)), asthenia (8%), and hand-foot syndrome (6%).

Both FRESCO and FRESCO-2 trials demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, and Progression Free Survival in patients with refractory metastatic colorectal cancer, when treated with Fruquintinib. This innovative therapy fulfills an unmet need and provides a new treatment option for this heavily pretreated group of patients.

Effect of Fruquintinib vs Placebo on Overall Survival in Patients with Previously Treated Metastatic Colorectal Cancer-The FRESCO Randomized Clinical Trial. Li J, Qin S, Xu R_H, et al. JAMA. 2018;319:2486-2496.

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Lancet. 2023;402:41-53. doi:10.1016/S0140-6736(23)00772-9.

LONSURF® (Trifluridine and Tipiracil ) with Bevacizumab

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The FDA on August 2, 2023, approved LONSURF® with Bevacizumab, for metastatic ColoRectal Cancer (mCRC) previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. FDA had previously approved single-agent LONSURF® for this indication in September 2015. LONSURF® is a product of Taiho Oncology, Inc.

FDA Approves LONSURF® with Bevacizumab for Advanced Refractory Colorectal Cancer

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SUMMARY: The FDA on August 2, 2023, approved LONSURF® (Trifluridine and Tipiracil with Bevacizumab, for metastatic ColoRectal Cancer (mCRC) previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil).

LONSURF® is a combination of two agents – a novel thymidine-based nucleoside analogue, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil. Trifluridine incorporates into DNA resulting in DNA damage and cell death. Trifluridine however is rapidly metabolized when taken orally and this is prevented by Tipiracil, which increases the bioavailability of Trifluridine. Single agent LONSURF® was approved by the FDA in 2015 for the treatment of patients with metastatic CRC, who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. This approval was based on the RECOURSE study, which is a pivotal, global, Phase III trial in which LONSURF® significantly improved Overall Survival as well as Progression Free Survival, when compared to placebo in this patient population.

Bevacizumab is a humanized monoclonal antibody that targets VEGF, a cytokine secreted by tumor cells and tumor-associated macrophages. VEGF is responsible for neoangiogenesis, proliferation, and metastasis, through its effects on endothelial cells. Bevacizumab was approved for the treatment of CRC in 2004. Maintenance of VEGF inhibition with Bevacizumab beyond disease progression has shown clinical activity in patients with metastatic CRC. A combination of LONSURF® in combination with Bevacizumab improved Overall Survival in several single-group and randomized Phase II trials.

The present FDA approval was based on SUNLIGHT trial, which is a multinational, multicenter, randomized Phase III study, designed to assess the efficacy and safety of LONSURF® in combination with Bevacizumab, as compared with LONSURF® alone, in patients with refractory metastatic CRC. In this study, a total of 492 patients with refractory metastatic CRC were randomly assigned in a 1:1 ratio to receive LONSURF® along with Bevacizumab (N=246) or LONSURF® alone (N=246). Patients received LONSURF® 35 mg/m2 orally, twice daily, on days 1-5 and on days 8-12 every 28 days. Bevacizumab was administered at a dose of 5 mg/kg IV on days 1 and 15. The 28-day treatment cycle was continued until disease progression or unacceptable toxicities. Bevacizumab monotherapy was not allowed. The two treatment groups were well balanced. Most patients (92%) had received two previous treatment regimens for metastatic disease, all patients had received previous Fluoropyrimidine-based therapy, 72% had received previous anti-VEGF therapy, 94% of the patients with RAS wild-type disease had received previous anti-EGFR therapy, and 30% had RAS wild-type disease. The Primary end point was Overall Survival. Secondary end points included Progression Free Survival, Objective Response and Disease Control Rate, Quality of Life and Safety. The median follow up was 14.2 months in the LONSURF® combination group and 13.6 months in the LONSURF® alone group.

The median Overall Survival was 10.8 months in the combination group and 7.5 months in the LONSURF® alone group (HR=0.61; P<0.001), suggesting a 39% reduction in the risk of death with the combination regimen. The median Progression Free Survival was 5.6 months in the combination group and 2.4 months in the LONSURF® alone group (HR=0.44; P<0.001). These benefits of LONSURF® plus Bevacizumab with respect to Overall Survival and Progression Free Survival were observed in all subgroups examined, including patients with poor prognostic factors. Survival benefits with the combination regimen were observed regardless of age, sex, location of primary disease, number of metastatic sites, RAS mutation status and previous treatment with Bevacizumab. The Objective Response Rate was 6.1% in the combination group versus 1.2% in the LONSURF® alone group. The median time to worsening of the ECOG PS from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the LONSURF® alone group (HR=0.54). The addition of Bevacizumab to LONSURF® did not increase the risk of serious adverse events or treatment discontinuation. The most common adverse events in both groups were neutropenia, nausea, and anemia.

It was concluded from this study that among patients with refractory metastatic colorectal cancer, treatment with LONSURF® plus Bevacizumab resulted in longer Overall Survival and Progression Free Survival, compared to LONSURF® alone, and this benefit was noted in all subgroups of patients.

Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. Prager GW, Taieb J, Fakih M, et al., for the SUNLIGHT Investigators. N Engl J Med 2023; 388:1657-1667

Tucatinib plus Trastuzumab for HER2-Positive Metastatic Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in 3-5% of patients with RAS wild-type metastatic colorectal cancer. HER2-positive tumors are IHC3+ by Immunohistochemistry (IHC) or IHC2+/FISH [Fluorescence in Situ Hybridization] amplified. Previously published studies have indicated that patients with HER2-positive CRC have less benefit from EGFR targeted therapies. In the HERACLES trial, a combination of two HER2 targeted therapies prolonged Overall Survival (OS) in RAS wild-type metastatic colorectal cancer.

Tucatinib (TUKYSA®) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2, with minimal inhibition of Epidermal Growth Factor Receptor. Trastuzumab (HERCEPTIN®) is a humanized monoclonal antibody targeting HER2/neu oncogene.

MOUNTAINEER is a U.S. and European multicenter, open-label, randomized, prospective, Phase II study, conducted among patients with previously treated HER2-positive metastatic colorectal cancer. This U.S. investigator-sponsored trial initially consisted of a single cohort (Cohort A) of patients who received Tucatinib 300 mg orally BID in combination with Trastuzumab 8 mg/kg IV given as a loading dose on Cycle 1, Day 1, followed by maintenance dose of Trastuzumab 6 mg/kg IV on Day 1 every three weeks thereafter. Patients were treated until disease progression or unacceptable toxicity. This trial was subsequently expanded globally to include patients who were randomized to receive Tucatinib plus Trastuzumab (Cohort B) or Tucatinib monotherapy (Cohort C). Eligible patients (N=114) were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with Fluoropyrimidine, Oxaliplatin, Irinotecan, and an anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody. Patients whose tumors were MisMatch Repair (dMMR) deficient or were MicroSatellite Instability-High (MSI-H) must also have received an anti PD-1 monoclonal antibody. Patients who received prior anti-HER2 targeted therapy were excluded. HER2 amplification was identified by Next Generation Sequencing in 61% of patients, by an IHC test score of 3+ in 40%, and by an IHC test score of 2+ and FISH amplification in 32%. The median age was 56 years, 58% were male, and 77% were Caucasian. Of patients who received combination therapy, 85% had left-sided primaries, 78% had received 2 or more lines of prior therapy, and 40% had received 3 or more lines of prior therapy. Over two thirds of the patients had liver or lung metastases. The Primary endpoint was Objective Response Rate (ORR) as assessed by blinded Independent Central Review (ICR) in patients receiving the combination of Tucatinib and Trastuzumab (Cohorts A and B). Secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS) and safety and tolerability of the combination regimen.

At a median follow up of 20.7 months, the ORR among Cohort A and B patients treated with a combination of Tucatinib and Trastuzumab (N=84) was 38.1% and the median Duration of Response was 12.4 months. The Disease Control Rate was 71.4%. The median Progression Free Survival was 8.2 months, and median Overall Survival was 24.1 months. In the Cohort C patients who received Tucatinib monotherapy (N=30), the ORR was only 3.3% and participants who did not respond to Tucatinib monotherapy by 12 weeks or had disease progressed at any time had the option to receive the combination of Tucatinib and Trastuzumab. Tucatinib in combination with Trastuzumab was well tolerated. Grade 1 or 2 diarrhea was the most common adverse event, followed by fatigue and nausea. Treatment discontinuation due to adverse events was low at 5.8%.

It was concluded that in this largest prospective trial to date among patients with chemotherapy-refractory HER2-positive, RAS wild-type metastatic colorectal cancer, Tucatinib in combination with Trastuzumab demonstrated durable and clinically meaningful antitumor activity and is a new chemotherapy-free treatment option for this group of patients. Based on these results, the FDA in January 2023, granted accelerated approval to Tucatinib in combination with Trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. Studies are underway investigating Tucatinib plus Trastuzumab in earlier lines of therapy.

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Strickler JH, Cercek A, Siena S, et al. The Lancet Oncology 2023;24:496-508.

Late Breaking Abstract – ASCO 2023: Avoiding Radiation Therapy in Select Patients with Locally Advanced Rectal Cancer

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SUMMARY: The American Cancer Society estimates that 46,050 new cases of rectal cancer will be diagnosed in the US in 2023. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

Management of invasive locally advanced rectal cancer, defined as Stage II (T3-4, N0) or Stage III (T1-4, N+) disease, mandates a multidisciplinary approach. Neoadjuvant chemoradiation therapy (CRT) followed by Total Mesorectal Excision (TME) and adjuvant chemotherapy is often recommended, whereas standard therapy for early-stage lesions involves surgery with or without adjuvant chemoradiation. The trimodality treatment approach was established as the standard of care for locally advanced rectal cancer based on the findings from the landmark German trial. Preoperative neoadjuvant CRT decreased the local recurrence rate in the pelvis from 25% to less than 10%. However, this treatment modality is associated with short-term and long-term toxicities and can adversely affect quality of life and physical function. With regards to chemotherapy, 4 months of adjuvant systemic chemotherapy following 2 months of Fluoropyrimidine-based chemotherapy with concurrent RT and surgery, is the recommended guideline by the National Comprehensive Cancer Network.

More recently, optimizing the delivery of therapy by intensifying neoadjuvant treatment has gained popularity. Moving chemotherapy from the postoperative (adjuvant) to the preoperative setting allows administration of full doses of systemic treatment with fewer adverse events and better compliance, assessment of the tumor response after neoadjuvant therapy, down staging tumors to increase the likelihood of pathological Complete Response (pCR) and complete resection, as well as opportunities for the selective omission of Radiation Therapy. Further, earlier administration of uninterrupted systemic chemotherapy can potentially eradicate occult micrometastases and help assess chemosensitivity.

FOLFOX chemotherapy regimen has been shown to be associated with high response rates when administered before chemoradiotherapy in patients with locally advanced rectal cancer. In a single institution study, neoadjuvant FOLFOX resulted in favorable outcomes, with few patients requiring radiation therapy and none of the patients developing local recurrence.

The PROSPECT trial is a multicenter, unblinded, noninferiority, randomized Phase III study, conducted to investigate whether neoadjuvant treatment with FOLFOX chemotherapy regimen could allow the elimination of chemoradiotherapy, without increasing the risk of recurrence, in patients with locally advanced rectal cancer that was amenable to sphincter-sparing surgery. This study was designed to test the hypothesis that neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by less than 20% or if FOLFOX was discontinued because of side effects) would be noninferior to neoadjuvant chemoradiotherapy alone, in patients with locally advanced rectal cancer that was amenable to sphincter-sparing surgery.

Eligible patients had pathologically confirmed, locally advanced rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive, and who were candidates for sphincter-sparing surgery. This group accounts for more than half the patients with a diagnosis of locally advanced rectal cancer in the United States. Patients with T4 tumors, four or more pelvic lymph nodes larger than 10 mm, or tumor visible within 3 mm of the radial margin seen on baseline pelvic imaging were ineligible. All patients had a pelvic MRI or contrast-enhanced CT of the chest, abdomen, and pelvis plus endorectal ultrasonography at baseline.

Patients were randomized 1:1 to neoadjuvant FOLFOX (N=585) or chemoradiotherapy (N=543). Patients in the FOLFOX group received 6 cycles of modified FOLFOX6 administered IV every 2 weeks, followed by restaging with pelvic imaging and rectal endoscopy. Patients whose primary tumor had decreased in size by at least 20% underwent surgery. Postoperative chemoradiotherapy was recommended for patients in the FOLFOX group whose resection was not pathologically complete (R0). Patients who were unable to complete at least five cycles of FOLFOX and those whose primary tumor had decreased in size by less than 20% also received chemoradiotherapy. Patients in the chemoradiotherapy group received pelvic radiotherapy with 50.4 Gy delivered in 28 fractions, along with either continuous infusion 5-FU chemotherapy given as a radiosensitizer at a dose of 225 mg/m2 daily or Capecitabine 825 mg/m2 orally twice daily, 5 days per week on days of radiation therapy. The median age was 57 years, a third of the patients were women and approximate 62% had clinically positive lymph nodes. Majority of tumors were in the mid-rectum, with a median distance of 8 cm from the anal verge The Primary end point was Disease Free Survival. Secondary end points included Overall Survival, local recurrence (in a time-to-event analysis), complete pathological resection, Complete Response, and toxicities.

At a median follow up of 58 months, FOLFOX was noninferior to chemoradiotherapy and the study met its Primary endpoint for DFS (HR for disease recurrence or death, 0.92; P=0.005 for noninferiority). Five-year DFS was 80.8% in the FOLFOX group and 78.6% in the chemoradiotherapy group. The Overall Survival was similar in the two treatment groups and the percentage of patients free from local recurrence was also similar in the two groups and exceeded 98% at 5 years. In the FOLFOX group, only 9.1% received preoperative chemoradiotherapy and only 1.4% received postoperative chemoradiotherapy. Over 89% of patients assigned to receive neoadjuvant FOLFOX were ultimately able to avoid receiving chemoradiotherapy.

The authors concluded that in patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX chemotherapy with selective use of chemoradiotherapy was noninferior to preoperative chemoradiotherapy with nearly identical outcomes. These data provide additional treatment options for this patient group without compromising efficacy, and toxicities associated with radiation therapy can be avoided.

Preoperative Treatment of Locally Advanced Rectal Cancer. Schrag D, Shi Q, Weiser MR, et al. June 4, 2023. DOI: 10.1056/NEJMoa2303269

LONSURF® Plus Bevacizumab Improves Overall Survival in Advanced Refractory Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil).

LONSURF® is a combination of two agents – a novel thymidine-based nucleoside analogue, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil. Trifluridine incorporates into DNA resulting in DNA damage and cell death. Trifluridine however is rapidly metabolized when taken orally and this is prevented by Tipiracil, which increases the bioavailability of Trifluridine. LONSURF® was approved by the FDA in 2015 for the treatment of patients with metastatic CRC, who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. This approval was based on the RECOURSE study, which is a pivotal, global, phase III trial in which LONSURF® significantly improved Overall Survival as well as Progression Free Survival, when compared to placebo in this patient population.

Bevacizumab is a humanized monoclonal antibody that targets VEGF, a cytokine secreted by tumor cells and tumor-associated macrophages. VEGF is responsible for neoangiogenesis, proliferation, and metastasis, through its effects on endothelial cells. Bevacizumab was approved for the treatment of CRC in 2004. Maintenance of VEGF inhibition with Bevacizumab beyond disease progression has shown clinical activity in patients with metastatic CRC. A combination of LONSURF® in combination with Bevacizumab improved Overall Survival in several single-group and randomized Phase II trials.

SUNLIGHT trial is a multinational, multicenter, randomized Phase III study, designed to assess the efficacy and safety of LONSURF® in combination with Bevacizumab, as compared with LONSURF® alone, in patients with refractory metastatic CRC. In this study, a total of 492 patients with refractory metastatic CRC were randomly assigned in a 1:1 ratio to receive LONSURF® along with Bevacizumab (N=246) or LONSURF® alone (N=246). Patients received LONSURF® 35 mg/m2 orally, twice daily, on days 1-5 and on days 8-12 every 28 days. Bevacizumab was administered at a dose of 5 mg/kg IV on days 1 and 15. The 28-day treatment cycle was continued until disease progression or unacceptable toxicities. Bevacizumab monotherapy was not allowed. The two treatment groups were well balanced. Most patients (92%) had received two previous treatment regimens for metastatic disease, all patients had received previous Fluoropyrimidine-based therapy, 72% had received previous anti-VEGF therapy, 94% of the patients with RAS wild-type disease had received previous anti-EGFR therapy, and 30% had RAS wild-type disease. The Primary end point was Overall Survival. Secondary end points included Progression Free Survival, Objective Response and Disease Control Rate, Quality of Life and Safety. The median follow up was 14.2 months in the LONSURF® combination group and 13.6 months in the LONSURF® alone group.

The median Overall Survival was 10.8 months in the combination group and 7.5 months in the LONSURF® alone group (HR=0.61; P<0.001), suggesting a 39% reduction in the risk of death with the combination regimen. The median Progression Free Survival was 5.6 months in the combination group and 2.4 months in the LONSURF® alone group (HR=0.44; P<0.001). These benefits of LONSURF® plus Bevacizumab with respect to Overall Survival and Progression Free Survival were observed in all subgroups examined, including patients with poor prognostic factors. Survival benefits with the combination regimen were observed regardless of age, sex, location of primary disease, number of metastatic sites, RAS mutation status and previous treatment with Bevacizumab. The Objective Response Rate was 6.1% in the combination group versus 1.2% in the LONSURF® alone group. The median time to worsening of the ECOG PS from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the LONSURF® alone group (HR=0.54). The addition of Bevacizumab to LONSURF® did not increase the risk of serious adverse events or treatment discontinuation. The most common adverse events in both groups were neutropenia, nausea, and anemia.

It was concluded from this study that among patients with refractory metastatic colorectal cancer, treatment with LONSURF® plus Bevacizumab resulted in longer Overall Survival and Progression Free Survival, compared to LONSURF® alone, and this benefit was noted in all subgroups of patients.

Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. Prager GW, Taieb J, Fakih M, et al., for the SUNLIGHT Investigators. N Engl J Med 2023; 388:1657-1667

ctDNA Analysis in Resectable Colorectal Cancer and Efficacy of Adjuvant Chemotherapy

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60–70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefiting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for resectable colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.

Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.

The GALAXY study/cohort is a part of the CIRCULATE-Japan project, and is a large prospective, observational study that monitors ctDNA status for patients with clinical Stage II-IV or recurrent colorectal cancer following curative-intent surgery. In order to prospectively validate and build upon the previously published evidence, the authors conducted this cohort study to demonstrate that postsurgical ctDNA positivity is predictive of disease recurrence in early-stage CRC. In this publication the researchers reported on postsurgical ctDNA positivity and its associations with patient outcomes, as well as its implications for adjuvant chemotherapy selection, and the association between ctDNA dynamics and prognosis.

The GALAXY study/cohort included 1039 patients with clinical Stage II-III colon cancer or surgically resectable clinical Stage IV or recurrent colorectal cancer. Eligible patients had histologically confirmed colorectal adenocarcinoma, and curative resection planned for clinical Stage II or III, and R0 resection planned for relapsed or Stage IV colorectal cancer. The median age was 69 years. Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue samples from surgical resection or biopsy were used for Whole Exome Sequencing (WES) to identify up to 16 patient-specific clonal, somatic Single-Nucleotide Variants (SNVs). These SNVs were then used to design personalized multiplex Polymerase Chain Reaction-based Next-Generation Sequencing assays (Signatera, Natera) for each study participant. Cell-free DNA was extracted from patient plasma at a given time point and was used to detect ctDNA. Plasma samples with at least 2 out of 16 tumor-specific variants detected above a predefined threshold were defined as ctDNA positive (tumor-informed ctDNA analysis. Overall, a total of 8,374 genes were selected for the 1,039 patients and the most frequently selected genes were TP53 (25.6%) and APC (17.5%). It was noted that more than 50% of genes were unique to each patient, suggesting large variability in the mutational landscape of colorectal cancer outside of known hotspot regions.

At a median follow-up of 16.74 months, postsurgical ctDNA positivity at 4 weeks after surgery was associated with higher recurrence risk compared to those patients who were ctDNA negative (61.4% versus 9.5%; HR=10.0, P< 0.0001) and the 18-month Disease Free Survival (DFS) was 38.4% versus 90.5%, respectively. This benefit was noted across all pathological stages. There was however no significant difference in recurrence risk by presurgical ctDNA status across all stages. In multivariate analysis for DFS in patients with pathological Stage II–III disease, ctDNA positivity 4 weeks after surgery was the most significant prognostic factor associated with increased risk for recurrence (HR=10.82, P< 0.001). Further, clinicopathological risk factors often used for staging and prognostication were nonsignificant. ctDNA was more valuable than CEA for relapse detection.

The researchers in this analysis examined the outcomes of ctDNA-positive and ctDNA-negative patients stratified by adjuvant chemotherapy status after adjusting for confounding variables such as age, sex, MSI status, pathological stage, and performance status in this analysis.

It was noted that patients with high-risk Stage II or Stage III disease and ctDNA-positive status 4 weeks after surgery derived significant benefit from adjuvant chemotherapy (adjusted HR=6.59; P< 0.001), and this trend was observed across all pathological stages. ctDNA-positive patients with Stage II–IV disease, not receiving adjuvant chemotherapy were noted to be at a higher risk for recurrence (adjusted HR=5.03; P< 0.001). Approximately 75% of ctDNA-positive patients with pathological Stage I or low-risk Stage II disease did not receive adjuvant chemotherapy and experienced recurrence.

Among the high-risk pathological Stage II or Stage III disease patients with ctDNA-negative status 4 weeks after surgery, there was no statistically significant benefit with adjuvant chemotherapy and the 18-month DFS was 94.9% and 91.5% for the adjuvant chemotherapy group and the observation group, respectively.

Among patients with available ctDNA status both 4 weeks and 12 weeks after surgery, there was a significantly higher risk of recurrence among patients who converted from ctDNA negative to positive, compared to those patients who were persistently negative (HR=14.0; P< 0.001).

Among the patients with ctDNA positivity 4 weeks after surgery, adjuvant chemotherapy was associated with a higher incidence of ctDNA clearance by week 24 after surgery compared with those who did not receive adjuvant therapy (68.48% versus 12.2%; adjusted HR=8.50, P< 0.0001). Among those who did not achieve ctDNA clearance, the DFS was inferior (adjusted HR=11; P< 0.0001).

Based on the results of this large and comprehensive prospective analysis of ctDNA in resectable colorectal cancer, the authors concluded that ctDNA status is a superior prognostic biomarker than the currently used high-risk clinicopathological features, and can identify patients who are at increased risk of recurrence and are likely to benefit from adjuvant chemotherapy.

Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Kotani D, Oki E, Nakamura Y, et al. Nature Medicine 2023; 29:127–134.

RNF43 Mutations

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RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic ColoRectal Cancer tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.