This month Manju and Maia cover a few highlights from the American Society for Clinical Oncology (ASCO) annual meeting that recently concluded in Chicago.

Manju discusses a few locally advanced non-metastatic rectal cancer trial results, while Maia talks about the DESTINY CRC-02 and NeoCol trials. She ends her section with a study that compares genomic alterations between early-onset and late-onset colorectal cancer.

Manju

Radiation may be safely omitted in select patients with locally advanced rectal cancer

PROSPECT: A Randomized Phase III Trial of Neoadjuvant Chemoradiation Versus Neoadjuvant FOLFOX Chemotherapy with Selective Use of Chemoradiation Followed by Total Mesorectal Excision for Treatment of Locally Advanced Rectal Cancer.

Abstract LBA2

This trial was initiated in 2012, when locally advanced rectal cancer was treated using the “classical” approach of chemoradiation, then surgery, after which patients got adjuvant chemotherapy. In this 1194 patient trial, researchers were looking at the role of radiation therapy as part of a neoadjuvant approach (given before surgery) to compare disease-free survival (DFS), overall survival, and side effect profiles.

The enrolled patients had intermediate risk, high or mid rectal tumors, which were cT1-T3 (these tumors had not grown into all the layers of the rectal wall) and node positive (or negative) tumors and were eligible for radiation treatment and sphincter-sparing surgery. The aim was to de-escalate treatment and skip radiation without compromising outcomes.

Patients were randomized 1:1 to the control arm, where patients got chemo-RT (radiation therapy), then surgery, and then adjuvant chemo. In the experimental arm, patients got six cycles of FOLFOX, after which they were restaged. If their tumors shrank by more than 20%, they had surgery next. If their tumors didn’t shrink as much, they got chemo-RT and then had surgery next. Patients in both arms got adjuvant chemo, but the regimen and cycle numbers were decided by the care team. In this trial, side effects were captured by both clinicians and patients. The trial had a non-inferiority design, which broadly means that the outcomes had to be comparable (less than 5% difference in five-year DFS) between both arms to be considered positive.

The trial was positive as each arm’s five-year local recurrence rates and DFS was quite close to that of the other arm. Pathologic complete response rates and the percentage of people who got chemo in each arm were also comparable. 9% of patients who received FOLFOX first also received chemo-RT, either because at restaging their tumors did not shrink enough, or they could not tolerate FOLFOX. The extent of side effects captured by clinicians and patients both showed side effects in each arm to vary before and after surgery. At 12 months post-treatment, they were comparable between each arm. Better bowel function and sexual function was seen in the FOLFOX group. The trial team concluded that neoadjuvant FOLFOX with chemo-RT only for those who needed it was shown as a safe and effective treatment option for a subgroup of rectal cancer patients.

For patients who are interested in skipping chemo-RT, it is very important to make sure that their tumor is quite similar to the group that had comparable benefits while skipping chemo-RT in the trial. Skipping chemo-RT may need to be balanced with the patient’s desire for non-operative management, which may require that patients get both chemo and chemo-RT as neoadjuvant treatment to shrink the tumor, so that it disappears completely thus allowing them to skip surgery.

This trial expands on the idea of personalized treatment strategies for locally advanced rectal cancer employing chemo, chemo-RT, and surgery as needed to get to the outcomes that are desired and clinically appropriate for each patient.

PRODIGE 23 trial, phase III; neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy, surgery, and adjuvant chemotherapy improved all outcomes, including overall survival, in patients with locally advanced rectal cancer compared with standard chemoradiotherapy, surgery, and adjuvant chemotherapy    

PRODIGE-23: Total Neoadjuvant Therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer 7-year results from PRODIGE-23

Abstract LBA3504 

The aim of the 461 patient PRODIGE-23 trial was to reduce distant metastases (metastases to organs far from the rectum), while preserving the low local recurrence rates seen with treatment for locally advanced rectal cancer.

The trial had two arms. The standard-of-care arm included chemoradiation, TME (total mesorectal excision surgery) seven weeks later and adjuvant mFOLFOX6 12 cycles or capecitabine for eight cycles. The experimental arm included induction chemo with mFOLFIRINOX with no bolus 5FU for six cycles, then chemo-RT followed by TME seven weeks later. Then patients got six cycles of mFOLFOX6 or four cycles of capecitabine.

Eligible patients were younger than 76, with MRI stage T3 or T4 rectal cancer with nodal involvement. The primary endpoint was disease-free survival, and the secondary endpoints were quality of life. The median follow up was 82.2 months. Here are the results from this trial at seven years.

Arm	7Y Recurrence rates	7Y Metastatic rates	7Y Disease- free survival	7Y Metastases-free survival	7Y Overall survival
TNT	5.3%	20.7%	67.6%	73.6%	81.9%
SOC	8.1%	27.7%	62.5%	65.5%	76.1%

In conclusion, induction chemo with mFOLFIRINOX before chemo-RT improves overall survival in locally advanced rectal cancer. The DFS and metastases-free survival is durable, and the quality of life is similar or improved with this approach. This is another option to consider for patients with locally advanced rectal cancer.

OPRA

Sustained organ preservation in rectal cancer patients treated with neoadjuvant therapy — Long-term results of the OPRA trial.

Abstract 3520

In this trial, patients with low lying locally advanced rectal cancer were randomized to an induction chemotherapy arm, where they get chemo first followed by chemo-RT (radiation therapy) versus a consolidation arm, where they get chemo-RT first, followed by chemotherapy. All patients were restaged at the end of this part and if they had a complete or near complete response (meaning the degree to which the tumor disappeared with treatment), they were offered watch and wait or non-operative management. With non-operative management, patients had the option of deferring surgery to only when there is a local regrowth. If they had an incomplete response, they were offered surgery at that time to remove the rectum along with the tumor.

The three-year OPRA trial results were presented at ASCO23 and show that there was no difference in disease-free survival (DFS) between the arms, but there was a significantly higher rate of organ preservation in the consolidation chemo arm.

At the median follow up of 5.1 years, 75% of patients in the trial were offered non-operative management and the rates were similar between both arms. 36% of patients developed local regrowth, with 44% in the induction arm versus 29% in the consolidation arm. The 5-year organ preservation rates (how many people got to keep their rectum) were 54% in the consolidation arm and 39% in the induction arm. When there was a local regrowth, a surgery called total mesorectal excision (TME) was done. There was no difference in five years DFS between TME at restaging (surgery upfront) versus TME at regrowth (salvage surgery later): Both were 64%. This shows that deferring surgery to only if there was a local regrowth did not affect the chances of being disease free at five years.

From these results, it seems that for locally advanced rectal cancer, if chemo is planned, it is safe and effective to have it neoadjuvantly (before surgery), and this greatly increases the chances of a cCR (complete clinical response: This means there are multiple methods to detect the tumor. For those patients who were able to pursue non-operative management, when they had surgery after local regrowth, it did not affect their chances of being disease-free at five years compared to those who had surgery upfront.

Maia

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study (NCT04744831)

Abstract 3501

Here is some news for HER+ metastatic colorectal patients (mCRC) that shows how sometimes “less is more.”

The international DESTINY-CRC02 randomized phase II clinical trial assessed the efficacy and safety of Trastuzumab deruxtecan (T-DXd, Enhertu^®) in patients with HER2-positive mCRC at two different doses (5.4mg/kg and 6.4mg/kg).

The study met its primary endpoint of confirmed objective response rate (cORR), with cORR in 37.8% in 82 patients who received the lower dose and 27.5% in the 40 patients treated with the higher dose. While some patients experienced grade 3 adverse events, overall safety was consistent with the known profiles of T-DXd. The results favor the lower dose as the optimal, single-agent regimen for this patient population.

Phase III randomized clinical trial comparing the efficacy of neoadjuvant chemotherapy and standard treatment in patients with locally advanced colon cancer: The NeoCol trial (NCT01918527)

Abstract LBA3503

The NeoCol trial was a phase III randomized study that compared the efficacy of neoadjuvant chemotherapy and standard treatment in patients with locally advanced colon cancer (that is, stage III with T3 and T4). "Neo" means "new”; "adjuvant" means "helper"; "neoadjuvant chemotherapy" refers to the chemo delivered before the main treatment (which in this case is surgery) to enhance it.

NeoCol was a large Danish clinical trial that lasted from 2013 to 2019. The results showed that disease-free survival (DFS) at two years was similar in the two arms, as was overall survival (OS). This suggests that neoadjuvant chemotherapy does not improve survival outcomes when compared to upfront surgery in patients with locally advanced colon cancer. On the other hand, there were slightly more postoperative complications in the standard group. Also after surgery, more patients in the standard arm had an indication of adjuvant chemotherapy (that is, chemo given to try to “mop up” any remaining cancer cells that might be left after the operation). In some cases, chemotherapy given before surgery induced downsizing of the tumor and downstaging. All this indicates that there are certain circumstances when receiving chemotherapy before surgery may have more favorable outcomes.

More analysis of the data from the trial is ongoing.

Evaluation of genomic alterations in early-onset versus late-onset colorectal cancer

Abstract 3511

A large study of early-onset colorectal cancer (EOCRC) patients was presented at ASCO 2023, which findings might open the door for personalization of therapy for these “too young for colorectal cancer” patients.

The research aimed to evaluate tumor genomic differences in patients with EOCRC, defined as CRC in patients age < 50, versus average-onset CRC (AOCRC) age > 60.

The cohort included over 13000 patients diagnosed with stages I-III colon or rectal cancer who had whole exome sequencing as part of their ctDNA (circulating tumor DNA) analysis with Natera's Signatera assay. This test is often referred to as “liquid biopsy,” since it is performed on a blood sample.

The study stratified its genomic analyses according to whether patients had high microsatellite instability (MSI-high) or were microsatellite stable (MSS), and considered also if they had high or low tumor mutation burden (TMB-high, TMB-low). (TMB is the number of changes (called genetic mutations) found in the DNA of cancer cells; it can be determined by lab tests that use next‐generation sequencing (NGS) methods.) The study also investigated the tumor mutations prevalent in each subgroup.

Most of the clinically meaningful tumor mutational differences between early-onset and average-onset patients were in the MSI-high/TMB-high and MSS/TMB-high subgroups. A detailed description of the findings is out of the scope of this blog post. But for example:

MSI-high/TMB-high subgroup, early-onset patients: The presence of HER2 and HER3 mutations was meaningful (15.8% of the patients in this subgroup had HER2 mutations, and 13.1% had HER3 mutations). This indicates the need to continue researching about the presence of HER amplifications (no mutations) in this subgroup, since there are emerging treatments for those.

MSS/TMB-high subgroup, early-onset patients: POLE mutations were present in almost 65% of early-onset patients; that is, 3.3% of all MSS tumors. POLE-driven tumors tend to be hypermutated, and patients with higher mutational burden tend to fare well with immunotherapy. Testing for TMB, especially in EOCRC patients, may lead to finding a new therapeutic option.

In simpler terms, this study found that there are unique differences in the genetic makeup of tumors in patients with EOCRC compared to those with AOCRC. These differences could potentially be used to develop new treatments for EOCRC.

Stay Tuned for More!

Once a month, Maia and Manju spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world!

You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials.

Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available. 

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community. 

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