Tanios Bekaii -Saab, MD

Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the unmet needs that are hoped to be filled by the phase 1/2 KRYSTAL-1 study (NCT03785249).

To be enrolled in the KRYSTAL-1 study, patients need to have a solid tumor with a 

 G12C mutation and unresectable or metastatic non-small cell lung cancer which progressed on or after treatment with a PD-1/PD-L1 inhibitor in combination with or following chemotherapy.

In part 1 of the study, the dose escalation of adagrasib (MRTX849) was reviewed, determining the maximum-tolerated dose to be 600 mg twice a day. Adagrasib at this dosage demonstrated a clinical benefit rate of 96% in the phase 1/1b trial and progressed to be the recommended phase 2 dose.

Because adagrasib showed promising clinical activity in this patient population, Bekaii-Saab hopes this study will help to fill some of the unmet needs that continue to exist in this space.

 KRYSTAL-1 is a study that's built as a phase 1, phase 1B and phase 2 study. The key criteria for entry on the study is essentially to have a 

 G12C mutation. Phase 1 was essentially dose escalation that primarily looked at trying to determine the maximum tolerated dose, 600 mg twice a day. That ultimately went into expansion and included some rational combinations. Phase 2 was monotherapy and combination. Phase 1B for example, had an added grasp for all solid tumors and for brain metastases, since it has that CNS penetration. They looked at lung cancers, both treatment naive and those that were exposed to prior 

 In colon cancer, these G12C inhibitors don't appear to have much activity on their own. That is because of a feedback loop mechanism that essentially creates that adaptive resistance and activates 

. In colon cancer, most of the follow through development was with adagrasib and cetuximab (Erbitux), which is what's being developed right now in a large study called KRYSTAL-10, a phase 3 randomized study looking specifically at adagrasib plus cetuximab plus chemotherapy in second-line colon cancer.

In pancreas cancer, they expanded from a single agent which is still ongoing but also to look at cetuximab plus. The phase 2 had a single agent in colon cancer plus cetuximab in colon cancer, then pancreas cancer plus cetuximab. The data I presented was on the other solid tumor basket. At the time, we presented with 42 patients with adagrasib, a single agent, and then there are lung cancer lung cancer cohorts, both single agents and one that includes the 

 mutations. There’s quite a bit of data that has been presented prior to the presentation I did at ASCO GI that included showing activity in lung cancer, colon cancer, the few patients with pancreas, ovarian, endometrial, phalangeal, you name it. Every cancer where this agent has been looked at, as long as they harbor the 

 G12C mutation, there has been evidence of activity.

Videos

Tanios S. Bekaii-Saab, MD, FACP, discusses the unmet needs that are hoped to be filled by the phase 1/2 KRYSTAL-1 study.

KRYSTAL-1 May Fill Unmet Needs in KRAS G12C mutated GI Cancers

: Which factors affect the treatment of patients with colorectal cancer (CRC)? Which tests do you usually order in this setting?

BEKAII-SAAB: The patient’s characteristics and age are important; whether they had prior adjuvant therapy; comorbidities; tumor burden. Is this a disease that you want to hit hard? Is this potentially resectable? It seems next-generation sequencing [is being done quite] liberally, but if you are limited by your choices, the first 4 [markers] you want on hand would be 

, microsatellite instability [MSI] high, and then HER2 amplifications. HER2 amplifications not only lead to HER2-targeted therapies at some point but also help eliminate the need for EGFR inhibitors, because 

amplifications predict for lack of efficacy of EGFR inhibitors. And, of course, patient preference [is also an important factor].

Which therapies do the National Comprehensive Cancer Network (NCCN) guidelines suggest?

The NCCN guidelines are a hodgepodge of [choices], and they really don’t limit you to 1 or 2 options. Pembrolizumab [Keytruda] is a first-line option for patients with MSI-high CRC given the results from KEYNOTE-177 [NCT02563002] that were presented at the American Society of Clinical Oncology [plenary session] and are now published as a paper in the 

What is your impression of this patient’s case so far?

It’s reasonable to do FOLFOX, although the preference would be for FOLFIRI [folinic acid, fluorouracil, and irinotecan]. Twenty percent to 30% will have a response, regardless of prior exposure, to oxaliplatin, as long as it’s been a while.

The patient started developing peripheral neuropathy—not too bad, though. But at this point, the patient has had enough oxaliplatin to consider the response as plateaued.

An old paper suggests that it doesn’t matter how you sequence FOLFOX or FOLFIRI; you get about the same benefit, and the same is true today.

What are the data supporting the use of regorafenib (Stivarga) for patients with CRC?

The phase 3 CORRECT trial [NCT01103323] was the initial study with regorafenib, which showed a median overall survival [OS] of 6.4 months [with regorafenib] versus 5.0 months for placebo [HR, 0.77; 95% CI, 0.64-0.94; 

 But the toxicities came early. In the first 2 weeks, you start seeing hand-foot syndrome, fatigue, and other toxicities like hypertension, which have limited the use. There have been a number of attempts to clinically [decrease these toxicities]; physicians have been using regorafenib every way they [could], starting with 80 mg or 120 mg, [to get to] 160 mg. There were not many data to help us understand a strategy to optimize the dose.

Some refer to [the ReDOS] study [NCT02368886] that we published in 

 in 2019, and it was a large phase 2 randomized study looking at regorafenib.

 It was [increased] from 80 mg to 120 mg to 160 mg on a weekly basis, weeks 1, 2, and 3, and then with a week off versus 160 mg [daily for] 3 weeks on, 1 week off. The study’s primary end point was a composite end point of efficacy and tolerability. In other words, patients were accounted for if they essentially got to cycle 3 and then continued beyond cycle 3. It means that they tolerated the drug [well] enough and they responded well enough.

The primary end point of the study was positive, where the dose-escalation strategy was superior to the standard-dose strategy. The OS was surprising; this was a secondary end point, [and we] thought survival wasn’t going to look much better, but it did look better with the dose-escalation strategy versus the standard dose, at 10 months versus 6 months, [respectively; HR, 0.72; 95% CI, 0.47-1.10; 

This changed the NCCN guidelines, and [regorafenib was added] as an option. Not only has this become the preferred way to give regorafenib in the United States, but it has become adopted across most of the world.

Can you discuss the trials for TAS-102 (trifluridine/tipiracil; Lonsurf)?

TAS-102 came on the heels of the RECOURSE study [NCT01607957] randomizing patients to TAS-102 versus placebo, with a primary end point of OS.

 There were similar trends with RECOURSE OS and progression-free survival [PFS] to what we’ve seen with regorafenib. There has never been a formal head-to-head comparison, but the results look similar.

The toxicity profile was a bit different. You see mostly neutropenia. In fact, 4% of patients [on regorafenib] had febrile neutropenia. I had a couple of patients over the past few years who ended up with febrile neutropenia and were admitted to the hospital. We often think about oral medications as less toxic from that standpoint.

 This study essentially was an indirect comparison, a network meta-analysis. What we found, essentially, is what you would expect. If you look at regorafenib 160 mg versus TAS-102, it’s pretty much a wash. OS and PFS hazard ratios were very similar, not much difference between the 2 [OS HR, 1.00; PFS HR, 0.93]. We also took the regorafenib schedule, the 80-plus mg, and compared it indirectly with historical best supportive care to confirm that it will maintain that value. The hazard ratios are impressive with this [OS HR, 0.44; PFS HR, 0.37]. When we compared regorafenib 80-plus mg with 160 mg from all randomized studies, regorafenib 80-plus mg maintained its advantage versus regorafenib 160 [OS HR, 0.65; PFS HR, 0.89]. We compared 80-plus mg with TAS-102—the 

 values were not positive, so it was just a numerical improvement with the 80-plus mg. Our conclusion was that there is definitely a trend for improved survival when you look at regorafenib 80 mg, 120 mg, and 160 mg versus regorafenib 160 mg or TAS-102, to be confirmed in larger trials, if that ever happens.

1. André T, Shiu KK, Kim TW, et al; KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699

2. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237. doi:10.1200/JCO.2004.05.113

3. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X

4. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refrac- tory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4

5. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMoa1414325

6. Sonbol MB, Benkhadra R, Wang Z, et al. A systematic review and network meta- analysis of regorafenib and TAS-102 in refractory metastatic colorectal cancer. Oncologist. 2019;24(9):1174-1179. doi:10.1634/theoncologist.2019-0189

Articles

During a virtual Targeted Oncology Case-Based Peer Perspectives event, Dr. Tanios Bekaii-Saab discussed the chemotherapy and targeted treatment options available for the treatment of patients with metastatic colorectal cancer with participating oncologists. 

Bekaii-Saab Explores Chemotherapies and Targeted Treatment Options in Metastatic CRC

Tanios S. Bekaii-Saab, MD, consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, discusses genetic testing and emerging precision medicine strategies in the field of colorectal cancer (CRC).

As part of the Academic and Community Cancer Research United (ACCRU) research consortium, multiple clinical trials are using genetic information obtained from roughly 6,000 patients with CRC across 16 centers. The study known as COLOMATE utilizes both liquid and tissue biopsy to identify genetic alterations in patients with CRC, say Bekaii-Saab. Other research includes the PULSE study (NCT03992456) of panitumumab (Vectibix), regorafenib (Stivarga), or TAS-102 (Lonsurf) as treatment of patients with metastatic and/or unresectable RAS wild-type disease. Finally, the MOUNTAINEER study (NCT03043313) of tucatinib trastuzumab in patients with HER2-positive disease is also underway as part of ACCRU. Presentations on these studies occurred during the 2021 Gastrointestinal Cancers Symposium.

Outside of these studies, Bekaii-Saab says there are basket trials that cover 

G12C-mutated disease. The hope is that the landscape continues to expand and CRC will become classified as multiple diseases based on the genetic alterations found in patients.

Tanios S. Bekaii-Saab, MD, discusses genetic testing and emerging precision medicine strategies in the field of colorectal cancer.

Tanios Bekaii -Saab, MD | Authors

Articles

KRYSTAL-1 May Fill Unmet Needs in KRAS G12C mutated GI Cancers

Bekaii-Saab Explores Chemotherapies and Targeted Treatment Options in Metastatic CRC

Genomics May Reclassify Disease in Patients With Colorectal Cancer