Immunotherapies As a Targeted Therapy To Accelerate Personalized Care

The overarching theme for this years ASCO Gastrointestinal Cancer Symposium was “accelerating personalized care.” So how well did we do? Did we accelerate or personalize care any better in gastroesophageal adenocarcinomas? Overall, we saw mixed results with important and promising preliminary data overshadowed by negative results from frontline maintenance approaches. We also got some early glimpses of how molecular technologies may truly accelerate and personalize care, particularly in the non-metastatic setting. 

In the opening session we saw the promise of leveraging biologic understanding to study early gastroesophageal cancer detection from cell-free DNA, and the potential for minimal residual disease (MRD) testing to inform adjuvant management. While both of these strategies require substantial prospective validation, they offer conceivable clinical impact in non-metastatic patients, where cure is possible. As shown with colon cancers and others, the blood-based detection of MRD using circulating tumor DNA can identify a group of patients at increased risk for disease recurrence where adjuvant intervention has a potential for larger clinical benefit. Similarly, the ability to sort out patients who may be considered for de-escalation of adjuvant therapy could reduce unnecessary exposure to toxic therapies. Several planned and ongoing clinical trials are using MRD testing to inform adjuvant management approaches and will be critical in validating MRD in gastric and esophageal cancers. 

Moving beyond early detection and management of locoregional disease, we saw negative results from the large phase III Javelin 100 trial in gastroesophageal cancers (1). This trial investigated the role of switch maintenance in untreated metastatic gastroesophageal cancers that had not progressed after 12 weeks of induction therapy with standard 5-fluorouracil. Non-progressing patients were randomized to chemotherapy or the anti-PD-L1 agent Avelumab and followed for the primary endpoint of overall survival. Roughly 800 patients began induction therapy and 500 had not progressed at 12 weeks and went on to randomization. The primary end point of overall survival in the intent to treat population was not met with an OS of 10.4 months with avelumab switch maintenance and 10.9 with continuation maintenance chemotherapy (HR = 0.91)(1). OS was longer on both arms in patients whose tumor cells expressed PD-L1, but there was no difference between the arms (HR = 1.13). Overall this is a sobering reminder of the OS in gastroesophageal adenocarcinomas and suggests a need for improved biomarker selection. The PLATFORM phase II trial paralleled the Javelin 100 findings and interim analysis did not demonstrate a clear increase in progression free survival with maintenance durvalumab compared to surveillance or maintenance 5-fluorouracil (2). If we were to consider immunotherapies as a targeted therapy best suited to targeted populations as we do for ALK or EGFR small molecule inhibitors, then perhaps we could achieve the acceleration of personalized care. We saw some support for this concept with the reporting of the MSI high (MSI-H) patients from Keynote 059, -061, and -062 by Dr. Joseph Chao and colleagues (3). MSI-high patients should be considered a targeted population and the overall response rate was ~50% or better across the multi-trial dataset spanning first line, second line, and third line disease settings (3). Although limited by sample size, the progression free and overall survival were prolonged in the MSI-H patients treated with pembrolizumab. This data lends substantial further support for the use of immune checkpoint inhibitors across the care continuum in MSI-H gastroesophageal adenocarcinomas.

There have been multiple efforts to expand the population of gastric and esophageal patients that benefit from immunotherapy approaches beyond those whose tumors are MSI-H and/or PD-L1 positive by the approved combined positive score method. Thus far, combinations with other immune checkpoint inhibitors and chemotherapy have met with disappointing results overall. However, at this year’s ASCO GI we saw some very encouraging preliminary data from Dr. Kohei Shitara and colleagues combining pembrolizumab with the multi-target kinase inhibitor lenvatinib in a phase II trial of mixed first- and second-line gastric cancer patients. Among the 29 patients the overall response rate was a robust 69% without clear evidence of enhanced or synergistic toxicities. Among the PD-L1 positive patients the ORR was 84% versus 40% in the PD-L1 negative patients (n = 10)(4). The same group also reported some updated results of the phase I REGONIVO trial taking a similar approach by combining the multi-target kinase inhibitor regorafenib with the anti-PD-1 agent nivolumab. The included patients had a median of three prior lines of therapy and the ORR was 40% across the cohorts with the combination (5). Recognizing the limited patient numbers and somewhat heterogenous populations these two datasets support further exploration and the hope that anti-angiogenic therapies in combination with immune checkpoint inhibitors can improve outcomes. The follow up studies for these promising combinations are eagerly awaited. 

Overall, there remain multiple unmet needs in gastroesophageal cancers, but with improving biologic understanding and molecular diagnostics, we increasingly have the tools to identify and learn from responders and non-responders. 

References

  1. Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC). J Clin Oncol 38, 2020 (suppl 4; abstr 278)
  2. Evaluating maintenance therapies in advanced oesophago-gastric adenocarcinoma (OGA): Interim analysis and biomarker results from the PLATFORM study. J Clin Oncol 38, 2020 (suppl 4; abstr 282)
  3. Pembrolizumab (pembro) in microsatellite instability-high (MSI-H) advanced gastric/gastroesophageal junction (G/GEJ) cancer by line of therapy. J Clin Oncol 38, 2020 (suppl 4; abstr 430)
  4. An open-label phase II study of lenvatinib plus pembrolizumab in patients with advanced gastric cancer (EPOC1706). J Clin Oncol 38, 2020 (suppl 4; abstr 374)
  5. Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603). J Clin Oncol 38, 2020 (suppl 4; abstr 135)

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