Atezolizumab/Bevacizumab Combo Attains 90% DCR in MSI-High mCRC

Howard S. Hochster, MD

Patients with microsatellite-high (MSI-high) metastatic colorectal cancer (mCRC) responded to an immunotherapy-containing regimen, according to results of a preliminary clinical evaluation presented at the 2017 Gastrointestinal Cancers Symposium.¹

In the open-label, multicenter phase Ib trial, the overall response rate was 40% through RECIST criteria and 30% via immune-related response criteria (irRC).

Four of 10 patients who were treated with the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) had partial responses (PRs) and 5 others had stable disease (SD). At a median follow-up of 14.8 months, neither the median duration of response (DOR) nor median progression-free survival (PFS) was reached.

Two patients each had grade 3/4 treatment-related adverse events (TRAEs). Four patients had TRAEs leading to discontinuation of treatment—3 involving bevacizumab and 1 involving atezolizumab.

“The combination of atezolizumab and bevacizumab was generally well tolerated and had a manageable safety profile,” lead author Howard S. Hochster, MD, professor of medicine at Yale School of Medicine, and colleagues concluded in a poster presentation.

“Atezolizumab and bevacizumab combination therapy shows encouraging antitumor activity in heavily pretreated patients with microsatellite instability-high mCRC,” he added. “In patients who respond to atezolizumab and bevacizumab, responses appear to be durable, with a median duration of more than 12 months. Further follow-up in this patient population is ongoing.”

Patients with treatment-refractory mCRC have a poor prognosis. In randomized clinical trial, treatment with the small-molecule inhibitor regorafenib (Stivarga) led to a median overall survival (OS) of 6.4 months, a 1.4-month improvement versus placebo.²

In the phase Ib trial reported at the meeting, Hochster and colleagues presented subgroup findings to evaluate the safety and pharmacology of combination therapy with atezolizumab and bevacizumab in patients with advanced solid tumors. The trial enrolled 10 patients with MSI-high mCRC.

The primary endpoint was safety and tolerability of the atezolizumab/bevacizumab combination. Secondary objectives included a preliminary assessment of antitumor activity of the combination by RECIST criteria and irRC.

Patients had a median age of 52.5, and all had an ECOG performance status of 0 to 1. Seven of the patients had received 2 or more prior lines of therapy for mCRC. Nine had treatment histories that included platinum-based chemotherapy, and 7 had previously received bevacizumab. Eight of the 10 patients had right-sided tumors.

By RECIST criteria and irRC, all but 1 of the patients achieved disease control (response or stable disease) with the combination. Four patients had a PR by RECIST versus 3 by irRC, and 5 patients had stable disease by RECIST, versus 6 by irRC.

Response duration ranged from 1.6 to 12.4 months by RECIST criteria and 7.8 to 12.4 months by irRC. PFS ranged from 1.5 to 21.9 months by RECIST and 2.6 to 23.7 months by irRC.

The most common TRAEs (all grades) were fatigue (n = 7), diarrhea (n = 5), proteinuria, arthralgia, and sinusitis (n = 4 each), anemia, hypertension, hypokalemia, and peripheral edema (n = 3 each), and nausea, noncardiac chest pain, small intestine obstruction, abdominal pain, anxiety, back pain, constipation, flank pain, muscle spasms, nasopharyngitis, pruritus, vomiting, and decreased weight (n = 2 each). Grade 3/4 TRAEs consisted of 1 case each of proteinuria, anemia, hypertension, hypokalemia, nausea, noncardiac chest pain, and small intestine obstruction.

MSI refers to the accumulation of mutations during DNA synthesis. Often arising as a consequence of mismatch repair (MMR) deficiency, MSI confers a poor prognosis. About 4% of patients with mCRC have an MSI-high phenotype.

Several studies have suggested that tumors with a high mutational burden are responsive to PD-1/PD-L1 inhibition. A study of patients with mCRC associated with MMR deficiency provided evidence of improved response among patients treated with PD-1 blockade as compared with patients whose tumors were MMR proficient.³

Bevacizumab, an angiogenesis inhibitor, targets vascular endothelial growth factor, which plays a role in cancer immune evasion. Antiangiogenic therapy has been shown to enhance immunotherapy effectiveness in cancer by normalization of the tumor vasculature.⁴ Bevacizumab was approved by the FDA in 2004 as a treatment for patients with mCRC.

References

1. Hochster HS, Bendell JC, Cleary JM, et al. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35 (suppl 4S; abstract 673).
2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
3. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
4. Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171-6180.