Combination Therapies and HER2-Targeted Agents Signal Favorable Responses in Gastrointestinal Cancers

Anne M. Noonan, MBBCh

Immunotherapy combinations, such as nivolumab (Opdivo) plus chemotherapy, as well as HER2-targeted therapies like fam-trastuzumab deruxtecan-nxki (Enhertu), are paving the way for increased survival rates across first-line and later stages of gastrointestinal (GI) cancers, according to Anne M. Noonan, MBBCh.

“The important thing to remember is that targeted therapies and immunotherapies are effective in patients with metastatic GI cancers, and it is promising to see advances,” Noonan said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on GI cancers, which she chaired.

In the interview, Noonan discussed prominent new therapies in hepatocellular carcinoma (HCC), the benefits of immunotherapy in gastric cancer, chemotherapy developments in pancreatic cancer, and the importance of considering HER2-targeted therapy in metastatic colorectal cancer (mCRC). She also previewed upcoming research with CAR T-cell therapy in gastric cancer and chemotherapy regimens in pancreatic adenocarcinoma.

Noonan is an assistant professor in the Department of Internal Medicine and chief of the Gastrointestinal Medical Oncology Section at The Ohio State University. She is also a member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center–James.

OncLive^®: Could you provide an outline of your presentation on advances in HCC and detail the findings from clinical trials studying atezolizumab (Tecentriq), bevacizumab (Avastin), and cabozantinib (Cabometyx) in this population?

Noonan: I discussed 4 recent studies that have led to some practice changes in relation to HCC. One was the [phase 3] IMbrave150 study [NCT03434379], which looked at atezolizumab and bevacizumab compared with sorafenib [Nexavar] in the first line. This trial was significant because it [led to] a new first-line option for our patients with HCC, given that the results were so good.

The median overall survival [OS] was 19.2 months for the combination of bevacizumab and atezolizumab compared with 13.4 months with sorafenib, the standard frontline option up to that point. That essentially led to this combination becoming 1 of our first-line options, now the preferred first-line option, in many cases.

The combination of bevacizumab and atezolizumab showed a response rate of 30% vs 11% for sorafenib. Additionally, 8% of patients had a complete response [CR], which [has historically been uncommon] in patients with HCC.

The other important point to note is that stable disease was also seen, with 74% of patients having disease control [with the combination]. The responses seemed to be durable, because 51% of those patients maintained that response 18 months or more after starting therapy.

The other trials I discussed were in relation to cabozantinib. Cabozantinib is a multi-targeted oral TKI. The [phase 3] CELESTIAL study [NCT01908426] demonstrated a manageable toxicity profile with cabozantinib when compared with placebo. The OS was 10.2 months with cabozantinib compared with 8.0 months in the placebo arm. This study allowed patients to have received more than 1 prior line of therapy, although they all must have been treated with sorafenib.

The investigators also did a subgroup analysis of the sorafenib-alone arm, and in those patients, who essentially had only the 1 line of therapy in the first-line setting, the OS was 11.3 months with cabozantinib vs 7.2 months with placebo. This trial gave us robust data to confirm that cabozantinib is a good option for patients in the second-line setting.

Your colleague, Ashish Manne, MBBS, of The Ohio State University Comprehensive Cancer Center–James, discussed the role of immunotherapy in gastric cancer, highlighting the phase 3 CheckMate 649 trial (NCT02872116), whichstudied immunotherapy plus chemotherapy vs chemotherapy alone in stomach cancer and gastroesophageal junction (GEJ) cancer. What are some benefits of chemoimmunotherapy in this patient population, and how do these data compare across patients with high and low PD-L1 combined positive scores (CPS)?

In the CheckMate 649 study, nivolumab plus chemotherapy was compared with chemotherapy alone. This was a positive study and showed that the addition of the immunotherapy improved OS compared with the chemotherapy-alone arm, with a 23% risk reduction. The combination of nivolumab with chemotherapy in the first-line setting resulted in a median OS of 14.0 months compared with 11.3 months with chemotherapy alone, which was statistically significant.

This study included patients who had a [PD-L1] CPS of greater than or equal to 1. However, in the subgroup analysis, it appeared that those who benefit the most are those whose [PD-L1] CPS is greater than or equal to 5. The addition of the immunotherapy improved outcomes overall with a manageable toxicity profile. This is becoming our standard option now for patients who have HER2-negative metastatic adenocarcinoma of the esophagus.

Dr Manne also talked about the phase 2 DESTINY-Gastric02 trial (NCT04014075). What survival benefits does trastuzumab deruxtecan provide to patients with HER2-positive gastric cancer?

This is a landmark study for our patients who have HER2-positive gastric and GEJ cancers. In this study, patients had previously received treatment with HER2-targeted therapy, including trastuzumab [Herceptin] and chemotherapy.

The results showed a median progression-free survival of 5.5 months, with a median duration of response of 8.1 months, which was significant for this population. The CR rate was 3.8%, with 34.2% of patients experiencing a partial response and 43% having stable disease. The clinical benefit was significant with this combination. [The regimen] seemed to be well tolerated in terms of the toxicity profile, with common adverse effects being nausea, fatigue, vomiting, diarrhea, and reduced appetite.

Laith Abushahin, MD, of The Ohio State University Comprehensive Cancer Center–James, shared pancreatic adenocarcinoma carcinoma data that were highlighted at the 2022 ASCO Annual Meeting. What did the phase 3 AVENGER 500 trial (NCT03504423)show about survival outcomes achieved with FOLFIRINOX and devimistat (CPI-613) in this population?

The AVENGER 500 trial was a study of modified FOLFIRINOX chemotherapy with the addition of devimistat, which selectively targets the altered form of mitochondrial energy metabolism and tumor cells. It was an interesting concept to try to improve outcomes in metastatic pancreatic adenocarcinoma. Unfortunately, the study did not show any difference in the primary end point of OS.

What was the significance of findings reported from the phase 1/2 SEQUENCE trial (NCT02504333), which Dr Abushahin also covered?

SEQUENCE was an open-label, randomized trial of first-line treatment in patients with metastatic pancreatic adenocarcinoma. The study randomly assigned 157 patients with an ECOG performance status of 0 or 1 to receive either nab-paclitaxel [Abraxane] with gemcitabine on days 1, 8, and 15 every 4 weeks until progression of disease or nab-paclitaxel with gemcitabine [on days 1, 8, and 15] followed by modified FOLFOX [(oxaliplatin, 5-fluorouracil, and leucovorin; mFOLFOX) on day 29] every 6 weeks.

The alternating sequence of nab-paclitaxel with gemcitabine followed by mFOLFOX showed an improvement in the median OS, which was 13.2 months vs 9.7 months for nab-paclitaxel and gemcitabine alone. This was an interesting study because the 12-month OS rate for the investigative arm was 55.3% vs 35.4% for the nab-paclitaxel and gemcitabine arm. Although this study was significant from the point of view of improving survival, it was small, and needs to be replicated [so the] results [can be verified].

John Hays, MD, PhD, of The Ohio State University Comprehensive Cancer Center–James, spoke about HER2-targeted therapy in mCRC, highlighting findings from the phase 2 HERACLES trial (NCT03225937). What interesting data came out of this trial regarding response rates with trastuzumab and lapatinib (Tykerb) vs pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla)?

One interesting aspect of the HERACLES trial was that, overall, it [showed HER2 to be] a viable target, with significant response rates in a population who would have been pretreated with FOLFOXIRI, FOLFOX, and FOLFIRI. Strikingly, the response rate in arm A, the trastuzumab and lapatinib arm, was 30%, and the response rate in arm B, the pertuzumab and T-DM1 arm, was 10%.

It is important from a clinical perspective to ensure that we check HER2 [status] in patients with mCRC because we have treatment options with response rates that are clinically significant and can affect a patient’s course.

What upcoming and ongoing research efforts in GI cancers are investigators from The Ohio State University Comprehensive Cancer Center–James participating in?

We are participating in several research studies. One interesting study that we are going to be opening shortly is [a phase 1b/2] trial [NCT04404595] from CARsgen Therapeutics, investigating CAR T-cell therapy targeting claudin 18.2. This trial is exciting because it’s going to enroll patients with metastatic gastric and GEJ cancers. [This therapy is] a new type of approach for solid tumors. Although [this approach] has been successful in hematologic malignancies, it’s still an ongoing area of investigation in solid tumors, so we’re excited to participate in this study. The gastric and GEJ cohort will be the cohort that we will be enrolling to, as they have paused the pancreatic arm.

An interesting clinical trial that we’re currently participating in is a [phase 2], investigator-initiated study [NCT04115163] designed by Dr Abushahin. It is a pilot study of a biologically optimized infusion schedule of gemcitabine and nab-paclitaxel in metastatic pancreatic adenocarcinoma. This study is for patients who are treatment naïve and who have metastatic pancreatic cancer. Essentially, the gemcitabine is given on day 1 and the nab-paclitaxel is given on days 3, 15, and 17. This study is based on data from researchers at The Ohio State University, and we’re excited to participate.

What main message encompasses the IPC meeting as a whole?

Some of these [promising immunotherapy and targeted therapy] agents are used on their own, others are more effective when combined with chemotherapy. Additionally, targets such as HER2 are important in the gastric and colorectal populations, and hopefully we will see results like what we have seen in the breast cancer population.