CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 29, 2023
Expiration: August 28, 2024
PROSPECT: Neoadjuvant Chemoradiation vs FOLFOX With Selective Chemoradiation for Locally Advanced Rectal Cancer
Rachna T. Shroff, MD, MS, FASCO:
The 2023 ASCO meeting presented data from numerous important trials, including the PROSPECT study.
Neoadjuvant chemoradiation has traditionally been a standard of care for patients with locally advanced rectal cancer.1 The underlying questions addressed in the PROSPECT trial were “Are there patients with locally advanced rectal cancer who could potentially avoid chemoradiation?” and “What is the utility, efficacy, and need for chemoradiation?”
The PROSPECT trial was a multicenter, randomized, noninferiority phase III study that compared neoadjuvant FOLFOX plus selective chemoradiation with neoadjuvant chemoradiation in patients with locally advanced rectal cancer—defined as stage T2 node positive or stage T3 node positive or node negative—who were candidates for neoadjuvant chemoradiation and sphincter preservation surgery (N = 1128).1,2 Chemoradiation was given to those in the FOLFOX treatment group only if the primary tumor decreased in size by <20% or FOLFOX was discontinued because of toxicity.
After completing the respective neoadjuvant approaches, patients were offered surgery, which typically involved an open or laparoscopic total mesorectal excision, followed by physician’s choice adjuvant therapy with FOLFOX or CAPOX.
The primary endpoint was DFS. The trial was not aimed at determining whether FOLFOX plus selective chemoradiation was more effective than chemoradiation, but rather sought to determine whether FOLFOX plus selective chemoradiation was noninferior to neoadjuvant chemoradiation.
Key secondary endpoints included local recurrence, OS, complete surgical resection, complete pathologic response, toxicity, and QoL.
PROSPECT: Baseline Characteristics
Rachna T. Shroff, MD, MS, FASCO:
In terms of baseline characteristics, most patients—50% in the neoadjuvant FOLFOX group and 57% in the chemoradiation group—had T3 node-positive tumors, meaning they had locally advanced cancer.1,2
PROSPECT: DFS
Rachna T. Shroff, MD, MS, FASCO:
The primary endpoint, DFS, was powered for noninferiority. Results demonstrated that the DFS Kaplan Meier curves for the neoadjuvant FOLFOX and chemoradiation groups essentially overlapped.1
The 5‑year DFS rates were similar between the groups, with an 80.8% DFS rate in the neoadjuvant FOLFOX group and a 78.6% DFS rate in the chemoradiation group (HR: 0.92).
PROSPECT: Freedom From Local Recurrence
Rachna T. Shroff, MD, MS, FASCO:
The freedom from local recurrence endpoint is important with respect to chemoradiation because it could be assumed that chemoradiation improves local recurrence rates. The local recurrence-free survival (RFS) rate at 5 years was similar between the treatment groups, with a 98.2% 5-year RFS rate in the neoadjuvant FOLFOX group and a 98.4% rate in the chemoradiation group.1,2
As with the DFS Kaplan Meier curves, the Kaplan Meier curves for freedom from local recurrence with the neoadjuvant FOLFOX and chemoradiation groups essentially overlap as well.
PROSPECT: OS
Rachna T. Shroff, MD, MS, FASCO:
At a median follow-up of 58 months, the groups demonstrated similar OS outcomes. The 5-year OS rate was 89.5% with neoadjuvant FOLFOX and 90.2% with chemoradiation.1,2
PROSPECT: Secondary Endpoints
Rachna T. Shroff, MD, MS, FASCO:
Other secondary endpoint results demonstrated similar complete (ie, R0) rectal resection rates and—of importance because sphincter preservation was a key issue in the trial—similar low anterior resection rates.1 This trial also demonstrated that pathologic complete response outcomes were similar between the treatment groups and that the positive radial margin rate was very low and similar between treatment groups.
Most patients in both groups received adjuvant chemotherapy. Among patients in the neoadjuvant FOLFOX group, only 9% actually received chemoradiation.
PROSPECT: HCP-Reported Toxicity
Rachna T. Shroff, MD, MS, FASCO:
The toxicities associated with both neoadjuvant chemoradiation and FOLFOX treatments are well known, and healthcare professionals (HCPs) are generally comfortable administering both regimens.
In the PROSPECT trial, neoadjuvant FOLFOX was associated with grade 3 or greater adverse events in 41% of patients, as reported by HCPs, compared with a 23% rate associated with chemoradiation. The grade 3 or greater adverse event rate with adjuvant therapy was similar between the treatment groups.1
During the neoadjuvant phase of the trial, diarrhea occurred more frequently in the chemoradiation group compared with the FOLFOX group, and neuropathy rates were higher in the FOLFOX group compared with the chemoradiation group
PROSPECT: Patient-Reported Toxicity
Rachna T. Shroff, MD, MS, FASCO:
Among patient-reported toxicities during the neoadjuvant treatment phase, diarrhea and neuropathy also stand out as being prevalent in the chemoradiation and FOLFOX groups, respectively. Fatigue was notable in both arms, with rates being somewhat higher in the FOLFOX group.2
PROSPECT: QoL
Rachna T. Shroff, MD, MS, FASCO:
Although not statistically significant, there was a trend toward improved QoL with neoadjuvant FOLFOX plus selective chemoradiation compared with chemoradiation alone.2
Bowel function and sexual function favored the neoadjuvant FOLFOX plus selective chemoradiation regimen over the chemoradiation regimen.2
PROSPECT: Conclusions
Rachna T. Shroff, MD, MS, FASCO:
The authors concluded that the phase III PROSPECT trial demonstrated that neoadjuvant FOLFOX chemotherapy plus, in 9% of patients, selective pelvic chemoradiation is safe and noninferior for DFS compared with neoadjuvant chemoradiation alone for patients with locally advanced rectal cancer.
The investigators noted an important caveat. Due to the trial’s prolonged nature, several novel treatment approaches for locally advanced rectal cancer emerged while the trial was ongoing, including shorter courses of adjuvant FOLFOX, which is based on the IDEA study3; short‑course radiation; total neoadjuvant therapy (TNT); and nonoperative management, including, for example, immunotherapy alone, which in the microsatellite instability-high rectal cancer setting has demonstrated tremendous responses without the need for surgery for many.
It is important to put the PROSPECT trial into the context of current treatment practices. I think the take‑home message from the trial is that certain patients may benefit from neoadjuvant chemotherapy instead of treating initially with chemoradiation. Sometimes patients need recovery time after surgery, so it is difficult to, for example, immediately give them 6 months of FOLFOX therapy. The PROSPECT trial suggests that by giving neoadjuvant FOLFOX therapy, some patients may possibly be spared from radiation therapy and its associated adverse events.
Christopher H. Lieu, MD:
I think that the PROSPECT trial is practice changing. I agree with Dr Shroff that, since the time the trial was initiated, there have been some changes in how locally advanced rectal cancer is treated. Specifically, Dr Shroff mentioned TNT, in which chemoradiation is typically followed by chemotherapy and then either surgery or, if the patient has achieved a complete clinical response, a watch-and-wait strategy. Having said that, I think the PROSPECT study is important because it shows that there is a cohort of patients with mid- to high-rectal cancer who do not need chemoradiation. This is significant because if we can provide comparable outcomes without the toxicities associated with chemoradiation, then this is a tremendous advance for our patients. Of specific concern is that chemoradiation induces early menopause and infertility in young patients. Therefore, avoiding radiation, including chemoradiation, especially in these patients may provide meaningful benefits. This is particularly relevant given that there is a higher incidence not only of early-onset colon cancer, but also of rectal cancer in the relatively younger population. Hence, being able to avoid chemoradiation in young women is extraordinarily important.
One caveat to this trial is that it does not address the watch-and-wait strategy, which is becoming an increasingly common strategy in addressing locally advanced rectal cancer. Watch and wait is important because a subset of patients who undergo TNT achieve a complete clinical response and do not require surgery. Another caveat is that the trial does not address low-lying rectal cancers that require an abdominoperineal resection with the creation of a permanent ostomy. For patients with these low-lying rectal tumors, chemoradiation is still recommended. Despite these caveats, I think the PROSPECT trial is practice changing because it suggests that we can provide similar outcomes with neoadjuvant FOLFOX chemotherapy while limiting the toxicities associated with chemoradiation for patients with locally advanced rectal cancer.
NORPACT-1: Neoadjuvant FOLFIRINOX vs Upfront Surgery in Resectable Pancreatic Head Cancer
Rachna T. Shroff, MD, MS, FASCO:
Data from the NORPACT-1 study, a randomized, unblinded, exploratory, multicenter phase II trial, also were presented at ASCO.4
This trial investigated whether using neoadjuvant FOLFIRINOX, which is one of the best perioperative regimens for pancreatic cancer, is beneficial compared with upfront surgery in patients with radiologically resectable pancreatic cancer.
As a pancreatic cancer physician, I am still uncertain about how to apply the results from this trial because my colleagues and I are currently starting to favor providing neoadjuvant therapy—typically chemotherapy—to patients with resectable or borderline resectable pancreatic cancer. In fact, it is my practice to give preoperative therapy to most every patient with resectable pancreatic cancer.
In the trial, 140 patients with resectable pancreatic head cancer were randomized to receive neoadjuvant FOLFIRINOX or upfront surgery. In the neoadjuvant FOLFIRINOX group, patients received 4 cycles of FOLFIRINOX and then were restaged. Patients who were still candidates for surgery underwent surgery and then received 8 cycles of adjuvant modified FOLFIRINOX (mFOLFIRINOX). In the upfront surgery group, after undergoing initial surgery, patients received 6 months—12 cycles—of adjuvant mFOLFIRINOX. The primary endpoint in this trial was OS.
NORPACT-1: Baseline Characteristics
Rachna T. Shroff, MD, MS, FASCO:
The treatment groups were relatively well balanced. It should be noted that among patients receiving neoadjuvant FOLFIRINOX, although 83% of patients started neoadjuvant therapy, only approximately one half—52%—completed neoadjuvant therapy.4 It will be important to understand why patients did not complete neoadjuvant therapy. In my experience, it is easier to give FOLFIRINOX before surgery rather than after a major Whipple surgery, so understanding the barriers to finishing the 4-cycle neoadjuvant regimen will be important.
It should also be noted that fewer patients in the neoadjuvant FOLFIRINOX group initiated adjuvant chemotherapy compared with those who underwent upfront surgery. It will be valuable to have additional data on these patients to determine why this was.
NORPACT-1: OS
Rachna T. Shroff, MD, MS, FASCO:
OS data were available from the ITT population and the per‑protocol population, which included all patients who received ≥1 cycle of neoadjuvant FOLFIRINOX or had undergone surgical resection.4 In the ITT population, the median OS was not significantly different between the treatment groups: Patients receiving neoadjuvant FOLFIRINOX had a median OS of 25.1 months, whereas patients who underwent upfront surgery had a median OS of 38.5 months. The HR was 1.52.
The 18-month OS rate also was not significantly different between treatment groups in the ITT population (60% among patients receiving neoadjuvant FOLFIRINOX compared with 73% among patients who underwent upfront surgery).
As in the ITT population, the median OS in the per-protocol population was different between treatment groups, but not statistically significant. However, it is a bit hard to argue with the differences between treatment groups that can be observed in the Kaplan Meier OS curves. It is possible that some of this difference is related to the size of the study.
NORPACT-1: Histopathology Outcomes
Rachna T. Shroff, MD, MS, FASCO:
In both the ITT and per-protocol populations, neoadjuvant FOLFIRINOX was associated with a higher percentage of R0 resection—56% and 59%, respectively—compared with the upfront surgery group, which had R0 resection rates of 39% and 33% in the ITT and per-protocol groups, respectively.4
Neoadjuvant FOLFIRINOX also was associated with higher rates of node-negative disease compared with upfront surgery. In the FOLFIRINOX group, 29% of patients in the ITT population and 37% in the per-protocol population were node negative compared with 14% and 10% of patients who were node negative in the ITT and per-protocol populations, respectively, in the upfront surgery group.
The long-term data regarding node-positive disease will be important, as node‑positive disease and R1 resections conventionally have been associated with an increased recurrence risk.
NORPACT-1: Safety
Rachna T. Shroff, MD, MS, FASCO:
In the NORPACT-1 safety population, 57.5% of patients in the neoadjuvant FOLFIRINOX group experienced grade ≥3 adverse events compared with 40.4% of patients in the upfront surgery arm. Grade 5 events appeared to be unrelated to treatment.4
NORPACT-1: Conclusions
Rachna T. Shroff, MD, MS, FASCO:
The NORPACT-1 investigators concluded that in patients with resectable pancreatic head cancers, neoadjuvant FOLFIRINOX did not improve OS compared with upfront surgery. Neoadjuvant FOLFIRINOX did demonstrate an acceptable safety profile and an improvement in R0 and N0 resection rates. The investigators acknowledged that longer follow‑up is needed to fully understand these outcomes but that current results do not support the use of neoadjuvant FOLFIRINOX as a standard of care in resectable pancreatic head cancer.
I think that although the data from this trial are provocative, the trial was limited in that it was a small phase II study that examined a selected population that included only patients with pancreatic head tumors. Of note, the presented data lacked information regarding FOLFIRINOX therapy completion and dose density.
I agree that longer‑term follow‑up is needed because robust data show that R0 matters—that a complete and total resection of microscopically negative margins matters for overall patient outcomes. Also, it is well established that patients with N1 node-positive disease are at higher risk for recurrence—usually systemic or distant metastatic—compared with patients with N0 node-negative disease.
Overall, the data from the trial are very intriguing, but a larger and more definitive trial is needed. I am interested to see results from the ALLIANCE A021806 trial, which is a large, randomized phase III trial. Like NORPACT-1, ALLIANCE is comparing neoadjuvant FOLFIRINOX with upfront surgery in patients with resectable pancreatic cancer (NCT04340141). Because ALLIANCE is large, with an estimated enrollment of 352 patients, it should be powered to definitively address the efficacy of neoadjuvant FOLFIRINOX therapy.
Christopher H. Lieu, MD:
I agree with Dr Shroff's conclusions about the NORPACT-1 trial. This trial is more hypothesis generating than it is practice changing. There is some concern that neoadjuvant chemotherapy may not be as effective as anticipated for patients with resectable pancreatic cancer, and the NORPACT-1 trial appears to support this concern. However, some of the patient characteristics in the trial create uncertainty with regard to the conclusions.
Some confusion stems from the fact that if patients had greater rates of R0 resection and less node-positive disease with neoadjuvant FOLFIRINOX, why would these patients also have worse outcomes?
Another interesting observation about the patient population in the NORPACT-1 study is that approximately 50% of patients did not receive the full amount of neoadjuvant FOLFIRINOX. In addition, approximately 50% of patients in the neoadjuvant FOLFIRINOX group did not complete the adjuvant protocol. Overall, there is some concern that the patient population in the neoadjuvant FOLFIRINOX group did not reflect what is typically seen in clinical practice.
However, I agree with Dr Shroff that the NORPACT-1 data are intriguing. NORPACT-1 is a precursor trial for 2 larger trials that are ongoing: the ALLIANCE trial mentioned above by Dr Shroff and a European perioperative FOLFIRINOX trial, PREOPANC-3 (NCT04927780). Overall, I do not think that practice should be changed based solely on the NORPACT-1 trial. Rather, I think that much more data will be available in the near future that should definitively answer the question of whether perioperative chemotherapy for resectable pancreatic cancer is superior to upfront resection followed by adjuvant chemotherapy.
HERIZON-BTC-01: Zanidatamab for Previously Treated HER2‑Amplified BTCs
Rachna T. Shroff, MD, MS, FASCO:
BTCs have become a model for precision oncology, and targeted therapies have changed the treatment landscape for these diseases.
BTCs comprise gallbladder cancers (GBCs), intrahepatic cholangiocarcinomas (ICCs), and extrahepatic cholangiocarcinomas (ECCs). HER2 amplifications are primarily observed in GBCs and ECCs, where approximately 10% to 15% of cases, respectively, demonstrate HER2 amplification. HER2 amplification occurs less frequently in ICCs.5,6
We will discuss data from 2 studies presented at ASCO that examined HER2-targeted therapies for treating advanced BTCs. The first study, HERIZON-BTC-01, was an open-label, single-arm phase IIb trial investigating the anti-HER2 bispecific antibody zanidatamab for patients with HER2-amplified, unresectable, locally advanced or metastatic BTC that had progressed on 1 or more gemcitabine-containing regimens (NCT04466891).7,8
The 87 patients in the trial were divided into 2 cohorts. The 80 patients in cohort 1 had traditional immunohistochemistry (IHC) 2+/3+ (ie, HER2-positive) BTC, and the 7 patients in cohort 2 had IHC 0/1+ BTC. All patients received zanidatamab every 2 weeks until progression. The primary endpoint was ORR.
HERIZON-BTC-01: Baseline Characteristics
Rachna T. Shroff, MD, MS, FASCO:
The cohort 1 population, the group of primary interest, was predominantly composed of Asian patients, which is typical in global BTC trials.
Just more than 50% of patients in cohort 1 had gallbladder cancers, which is also typical. However, the 30% of patients with ICCs is higher than what is normally observed. Approximately three quarters of patients—78%—had an IHC 3+ HER2 status.7,8
HERIZON-BTC-01: Response
Rachna T. Shroff, MD, MS, FASCO:
At the time of data cutoff, 16 patients in cohort 1 had an ongoing response, and the ORR was 41.3%.7,8
To give some context to the significance of these results, the standard-of-care, first-line combination of gemcitabine, cisplatin, and durvalumab has been associated with an ORR of 27% in patients not selected for HER2 status. So, in refractory patients, this was exciting.9
Equally exciting was that the disease control rate was 68.8% and the median duration of response (DoR) was 12.9 months, which is quite long for BTCs.7,8 It is also important to note that the median time to first response among patients in cohort 1 was 1.8 months, meaning that, in addition to being durable, responses were rapid. Results also demonstrated that, regardless of subgroup, most patients derived benefit from zanidatamab.
HERIZON-BTC-01: Change in Target Lesion Size
Rachna T. Shroff, MD, MS, FASCO:
In cohort 1, 68.4% of patients experienced a decrease in target lesion size.7,8 This means that even though the ORR was approximately 40%, most patients experienced some sort of benefit in the form of decreased tumor burden.
The observed decrease in target lesion size was observed across all BTC subtypes—GBCs, ECCs, and ICCs.
HERIZON-BTC-01: PFS (Cohort 1)
Rachna T. Shroff, MD, MS, FASCO:
Progression-free survival (PFS) in cohort 1 was 5.49 months. This is not particularly exciting, however, the PFS among patients with refractory BTCs is typically short—approximately 2 or 3 months—with chemotherapy regimens.7,8
HERIZON-BTC-01: Safety
Rachna T. Shroff, MD, MS, FASCO:
In the safety population, no grade 4 or 5 adverse events were reported, and dose reductions were necessary in only 3 patients due to diarrhea.7,8
Diarrhea is a well-established adverse event associated with HER2-targeted therapies.10 In the trial, grade 1/2 diarrhea occurred in approximately 32% of patients, and only approximately 5% of patients experienced grade 3 diarrhea. However, it is important to note that in practice, even grade 2 diarrhea can be clinically meaningful to patients.
Infusion‑related reactions were also a common adverse event. Grade 1/2 infusion-related reactions were reported by 32% of patients.7,8
Ejection fraction decrease is another established adverse event associated with HER2-targeting therapies.11 Grade 1/2 and grade 3 events occurred in 6% and 3% of patients, respectively.7,8
HERIZON-BTC-01: Adverse Events of Special Interest
Rachna T. Shroff, MD, MS, FASCO:
Of importance, confirmed cardiac event rates were low, with any-grade events occurring in 6.3% of patients and grade 3 events occurring in 3.8% of patients.7,8
HERIZON-BTC-01: Conclusions
Rachna T. Shroff, MD, MS, FASCO:
Investigators concluded that zanidatamab was associated with rapid and durable responses for patients with HER2-amplified, locally advanced, unresectable or metastatic BTCs, with an ORR of 41.3% and a DoR of 12.9 months. Zanidatamab was also associated with a very manageable safety profile, suggesting that it could be a treatment option for patients with HER2-amplified BTCs.
Christopher H. Lieu, MD:
This study demonstrated rapid and durable responses with zanidatamab and an impressive ORR and DoR. I think that this trial emphasizes the importance of early biomarker testing in patients with BTCs, as these are rapidly becoming biomarker-driven diseases. With regard to HER2-targeted therapies, data are accumulating that show the efficacy of these therapies in HER2-amplified BTCs.
Zanidatamab has a unique mechanism of action, and it will be interesting to see what happens with regard to its approval for HER2-positive BTCs. A caveat of this trial is that it examined a relatively small population with a single arm.
The results showed that not only were the responses significant—especially compared with second-line and beyond chemotherapy, which is associated with extremely low response rates—but the DoR also was impressive. Overall, I think that any time there is an opportunity to use a targeted therapy that may have a better toxicity profile and improved efficacy compared with chemotherapy, then it is a really exciting development and potentially an exciting treatment for the future for our patients.
Tucatinib Plus Trastuzumab for Previously Treated, Advanced, HER2-Positive BTCs
Rachna T. Shroff, MD, MS, FASCO:
In addition to zanidatamab, another novel HER2-targeting therapy is tucatinib, which is a highly selective, HER2-targeted tyrosine kinase inhibitor. At ASCO 2023, data were presented from a cohort of an open-label, single-arm phase II basket trial in which patients with HER2-positive (IHC 3+/next-generation sequencing), unresectable, locally advanced or metastatic BTCs who had progressed on 1 or more lines of systemic disease received tucatinib plus trastuzumab (NCT04579380).12 The primary endpoint of the trial was ORR.
Tucatinib Plus Trastuzumab for HER2+ BTC: Baseline Characteristics
Rachna T. Shroff, MD, MS, FASCO:
Like the HERIZON-BTC-01 trial, patients were primarily Asian, and approximately 50% had gallbladder cancer. Among the remaining 50% of patients, there was almost an even split between those who had intrahepatic cholangiocarcinoma (23.3%) and those who had extrahepatic cholangiocarcinoma (26.7%).12
Tucatinib Plus Trastuzumab for HER2+ BTC: Response
Rachna T. Shroff, MD, MS, FASCO:
Among the 29 evaluable patients, most—approximately 70%—experienced a reduction in tumor size, with an ORR of 46.7%.12
The median DoR was 6 months and the time to response was 2.1 months.7,8,12
Tucatinib Plus Trastuzumab for HER2+ BTC: PFS and OS
Rachna T. Shroff, MD, MS, FASCO:
The tucatinib plus trastuzumab combination was associated with a median PFS of 5.5 months.7,8,12 The median OS among patients receiving the tucatinib plus trastuzumab combination was 15.5 months.
Tucatinib Plus Trastuzumab for HER2+ BTC: Safety
Rachna T. Shroff, MD, MS, FASCO:
Grade ≥3 treatment‑emergent adverse events (TEAEs) occurred in 60% of patients, but only approximately 10% of patients discontinued treatment due to TEAEs.12
Tucatinib Plus Trastuzumab for HER2+ BTC: TEAEs in ≥10% of patients
Rachna T. Shroff, MD, MS, FASCO:
Among the TEAEs, diarrhea was a significant issue, occurring in 40% of patients. Most cases (33.3%) were grade 1/2, but from the patient perspective, grade 2 can be clinically meaningful.12
Tucatinib Plus Trastuzumab for HER2+ BTC: Exploratory Analyses of HER2 Testing and Response
Rachna T. Shroff, MD, MS, FASCO:
During an exploratory analysis, the investigators demonstrated that, although there was not 100% concordance between local testing and central confirmation of HER2 amplification, the rate was 87.5% when central IHC or fluorescence in situ hybridization was used, which was relatively high
Tucatinib Plus Trastuzumab for HER2+ BTC: Conclusions
Rachna T. Shroff, MD, MS, FASCO:
The investigators demonstrated that the tucatinib plus trastuzumab combination was associated with an ORR of 46.7% in patients with advanced HER2- amplified/overexpressing BTC, which is exciting; a tolerable safety profile also was observed.
The trial also suggests that, although there are various HER2 testing methods, central confirmation may not always be necessary.
Overall, I think a key takeaway from both this trial and the HERIZON-BTC-01 trial is that it is important to identify HER2 amplifications in patients with BTCs because HER2-directed therapies for these cancers eventually will become available.
Christopher H. Lieu, MD:
As Dr Shroff discussed, this trial demonstrated an impressive response rate, a meaningful DoR, and a very tolerable safety profile.
Also, this trial emphasizes the importance of biomarker testing in patients with BTCs. Depending on the location of the metastases and the primary tumor, it is sometimes difficult to acquire tumor tissue from these cancers. However, even though it may be difficult, it is extremely important to obtain sufficient tissue for molecular testing. Alternatively, if tumor tissue cannot be acquired, circulating tumor DNA can be used for biomarker testing.
Overall, the activity of chemotherapy in refractory BTCs is unimpressive. Being able to offer targeted therapy to patients with these cancers, including HER2-targeted therapies, will be incredibly beneficial.
A current caveat is that many HER2-targeted therapies are not approved by the FDA for treating BTCs. However, given the data emerging from this single-arm trial and the HERIZON-BTC-01 single-arm trial showing high response rates in a rare patient population, it will be interesting to see if therapies receive approval in the future
CodeBreaK 101: Sotorasib Plus Panitumumab and FOLFIRI for Previously Treated KRASG12C-Mutated mCRC
Christopher H. Lieu, MD:
Historically, KRAS mutations in colorectal cancer have been considered to be “undruggable,” with the KRASG12C mutation associated with a poorer prognosis in colorectal cancer.13 However, recently there has been emerging evidence for using KRASG12C inhibitors in metastatic colorectal cancer (mCRC).
For example, data were presented at ASCO 2023 from CodeBreaK 101, an open-label, nonrandomized, multi-arm phase Ib/II trial evaluating sotorasib, a KRASG12C inhibitor, as monotherapy and in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRASG12C mutation (NCT04185883).
Data from ASCO 2023 were presented from an arm of the study examining a combination of sotorasib plus panitumumab plus FOLFIRI in 33 patients with KRASG12C-mutated mCRC who had received 1 or more prior lines of therapy for metastatic disease. The primary endpoint was safety, with secondary endpoints including efficacy and pharmacokinetics.14 The trial demonstrated that the sotorasib plus panitumumab plus FOLFIRI combination was associated with a tolerable safety profile and significant efficacy, with an ORR of 58%.
There are 2 main takeaways from the trial. First, there will be an increasing number of these trials of combinations of chemotherapy and targeted agents as first-line and second-line regimens. Second, with increasing evidence showing the efficacy of KRASG12C inhibitors in KRASG12C-mutated mCRC, it is important that patients with mCRC undergo early and robust molecular testing. Early in their treatment, patients with KRASG12C-mutated mCRC also should be strongly considered for clinical trial enrollment because there are currently no FDA-approved therapies in this space.
Additional GI Cancer Studies of Note at ASCO 2023
Additional studies of interest in GI cancers included the following.
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