Faculty Bibliography

Background: Novel strategies to improve the efficacy of immune checkpoint inhibitors in microsatellite stable (MSS) mCRC are needed. CV301 is a vector-based vaccine that expresses carcinoembryonic antigen (CEA) and mucin 1 (MUC1), and in a phase II study in resected hepatic limited mCRC significantly improved OS compared with unvaccinated contemporary controls.
Method(s): In this multicenter randomized phase II study, patients with previously untreated resectable hepatic-limited mCRC were randomized to perioperative nivolumab + mFOLFOX +/- CV301 (Arm B) with a primary endpoint of 3-year OS. Treatment included mFOLFOX-nivo (+/- CV) x 4 cycles followed by resection, then 8 more cycles of mFOLFOX-nivo followed by maintenance nivo monthly for two years in both arms, and CV boosters concurrently with mFOLFOX, and then every 3 months for two years in arm B. Secondary endpoints of ORR (following induction pre-resection), PRR, and safety were determined. Correlative analyses included immune cell quantification using Immunoscore and T-cell clonality.
Result(s): 17 patients were enrolled prior to premature closure for slow accrual (8 arm A, 9 arm B). At the time of data cutoff, 5 patients remained on treatment and no deaths had occurred. One patient was removed from study due to protocol non-compliance. The median age was 61, majority were male (59% vs 41%), and ECOG PS 0-1 (71% 0, 17% 1). All patients had complete surgical resection. Four patients (24%) experienced a SAE related to drug. The TRAE rate was 40.3%,. No AEs delayed/prevented surgical resection. The ORR in arm A was 50% (including 4 CR) and 87.5% in arm B (including 7 CR) (p=0.129, NS). There was no significant difference in pathologic response (p=0.9047). Correlative analyses demonstrated the Immunoscore CD3/CD8 predicted response to mFOLFOX + nivolumab, but did not correlate with response to CV301, though CV301 may induce a shift to predominantly cytotoxic CD8+ T cells. While there was no significant difference in T cell repertoire, clonality, fraction (TCFr) or richness, patients in arm B had significant decreases in blood TCFr and increase in tumor TCFr with treatment; those with CR had higher TCFr and clonality.
Conclusion(s): The addition of CV301 to perioperative nivolumab and mFOLFOX was safe, did not delay or prevent surgical resection, and gave a higher response (p=ns due to sample size). Changes in T cells suggest a vaccine response. (Table Presented)

Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response.
Method(s): Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors.
Result(s): 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 - 18) with 9 (28%) pts more than 6 months.
Conclusion(s): In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting

Esophageal cancer is the eighth most common cancer worldwide and is the sixth most common cause of cancer-related mortality. The paradigm has shifted to include a multimodality approach with surgery, chemotherapy, targeted therapy (including immunotherapy), and radiation therapy. Advances in radiotherapy through techniques such as intensity modulated radiotherapy and proton beam therapy have allowed for the more dose homogeneity and improved organ sparing. In addition, recent studies of targeted therapies and predictive approaches in patients with locally advanced disease provide clinicians with new approaches to modify multimodality treatment to improve clinical outcomes.

BACKGROUND:Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS:Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS:35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION:Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.