AACR 2020 Conference – Opening Clinical Plenary Highlights

In light of the COVID-19 pandemic that has swept the world currently, earlier this month, the board of directors of the American Association for Cancer Research (AACR) announced their unprecedented decision to convert this year’s in-person Annual Meetings into two AACR Virtual Annual Meetings. Part I of the virtual conference is available for free and will be held on April 27th and 28th, 2020. Below, we present the highlights of the opening clinical plenary session on day 1.

Cancer is a major public health concern and is one of the leading causes of global mortality, just below heart diseases. Multiple approaches such as surgery, radiation, and chemotherapy have been employed over time with mixed results. In recent times, the endeavor of turning one’s own immune cells against cancer has revolutionized cancer treatments, marking the arrival of immunotherapies. Immune checkpoint inhibitors, Chimeric Antigen Receptor T cells (CAR-T), and lately, Chimeric Antigen Receptor-Natural Killer Cells (CAR-NK) have all captured the attention of the community with their promise and improved efficacy.

Although the durability and response rates have significantly improved, these interventions are not without their share of limitations. Several patients still do not respond to immunotherapies due to mounting challenges like tumor resistance, heterogeneity, and antigen escape. As a result, combinatorial strategies, merging the attributes of different interventions have now become more common. It involves the synergistic combinations of immunotherapy agents or combining immunotherapy agents with standard chemotherapy and/or molecularly targeted therapy. The opening plenary session of the Virtual AACR conference featured the results of four such studies that tested combinatorial approaches.

AZ’s Imfinzi, Lynparza Combo Improves Outcomes in Breast Cancer

Imfinzi is an FDA-approved, immune checkpoint Inhibitor for bladder and lung cancers. However, emerging results suggest its benefit as a single agent in breast cancer and it is also considered for combinatorial approaches. I-SPY2, a Phase 2 trial, aimed to identify novel drug agents that synergistically combined with targeted therapies to work against different breast cancer types.

In this study, Imfinzi (durvalumab) was combined with the PARP inhibitor, Lynparza (olaparib) based upon the following preclinical rationale. PARP inhibition impairs cancer’s DNA repair pathways leading to increased mutations. The resultant high neoantigen load of tumors would activate the STING pathway boosting host immune responses. Besides, PARP inhibitors increase the PD-L1 expression in breast cancers, and combining these two classes of inhibitors has shown promising data earlier.

Results suggest that in comparison to chemotherapy alone, the combination of durvalumab, olaparib, and chemo drug paclitaxel (collectively DOP), significantly improved the pathologic complete response (pCR) in women with stage II/III, high risk, HER2 negative breast cancer (22% vs. 37%) and in two other subsets, HER2-negative/ER-positive (14% vs. 28%) and triple-negative breast cancer (TNBC) (27% vs. 47%).

The results were presented by Prof. Lajos Pusztai from Yale University. All 73 patients in the DOP arm received three doses of 1500 mg durvalumab every four weeks, olaparib 100 mg twice daily through weeks 1–11, weekly administration of paclitaxel 80 mg/m2 for 12 weeks, followed by four cycles of doxorubicin/cyclophosphamide (AC). No unexpected safety signals were observed, and the adverse events were consistent with known side effects.

Roche’s Tecentriq Combo with BRAF & MEK inhibitors Shows Promise in Advanced Melanoma

BRAF inhibitors (BRAFi) like Zelboraf (vemurafenib) have been the standard treatment for advanced melanoma that harbors BRAF V600E substitutions. It has been frequently combined with MEK inhibitors (MEKi) like Cotellic (cobimetinib) to improve efficacy.

Preclinical data suggest that the combination of BRAFi and MEKi can lead to an influx of T cells into the tumors, decrease suppressor cells, and upregulate melanoma antigens. Although this combination improves overall response rates, it is short-lived in patients due to acquired resistance. In contrast, immune checkpoint inhibitors display lower response rates but are more durable. Therefore the combination of these two approaches was tested.

Last December, Roche announced that its IMspire150 trial, which evaluated Tecentriq (atezolizumab) plus Cotellic and Zelboraf met its primary endpoint. The lead author of the study, Prof. Grant McArthur from the Peter MacCallum Cancer Centre in Melbourne, presented the results in the opening plenary.

Data suggests that the Tecentriq combo produced durable responses and significant improvement in investigator-assessed progression-free survival (PFS) as compared to placebo plus Cotellic and Zelboraf (15.1 vs. 10.6 months). While the objective response rates were similar for both cohorts, the median duration of response was prolonged in the Tecentriq arm (21 vs. 12.6 months).

Continuous Dosing of BRAF and MET Inhibitors Improves Survival

As mentioned earlier, the efficacy of BRAFi and MEKi combo is brief due to the acquisition of resistance. Preclinical data suggest that an intermittent dosing regimen may delay this issue. Therefore the randomized, Phase 2 clinical trial, S1320, was designed to determine whether intermittent dosing of dabrafenib (BRAFi) and trametinib (MEKi) improved outcomes in patients with advanced BRAF V600E/K melanoma as opposed to continuous dosing.

The lead author, Dr. Alain P. Algazi, from the University of California at San Francisco, presented results from the study. A total of 242 patients received continuous dosing of both inhibitors for eight weeks. Following that, 206 patients without disease progression were randomized into two groups that either received continuous (105) or intermittent treatment (101) of both drugs on a 3-week-off, 5-week-on schedule.

Contrary to expectations, the intermittent dosing group showed a median PFS of just 5.5 months as compared to the 9.0 months with continuous dosing (p = 0.064). There was no difference in overall survival between the groups (median OS = 29.2 months in both arms p = 0.93) at a median follow-up of 2 years.

The consensus among the experts was that this unexpected result might have been due to the half-life of trametinib, which is four days. Dr. Algazi said that there are preclinical data suggesting that a rapid decrement in drug levels is required to get effective tumor killing in drug-addicted cells. The long half-life of trametinib may have precluded this effect. He also gave alternative explanations to this effect citing lesser drug exposure in the intermittent dosing arm or the existence of resistance pathways other than the well-known MAP kinase pathway.

Tecentriq Xtandi Combo Fails to Extend Survival in Prostate Cancer

Xtandi (enzalutamide) is an androgen receptor agonist that was initially FDA approved for treating metastatic castration-resistant prostate cancer (mCRPC). Since then, it has also scored approvals for extended indications, including non-metastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Roche wanted to test whether immune checkpoint inhibition with Tecentriq can offer extra benefit. It hypothesized that Xtandi may enhance IFNɣ signaling and sensitize tumor cells to immune-mediated cell killing. However, the Phase 3, IMbassador250 trial, which is the first study to evaluate checkpoint inhibitor combination in mCRPC patients, did not yield anticipated results.

Dr. Christopher J. Sweeney, MBBS, medical oncologist at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School presented the data. A total of 759 patients with no prior treatments were randomized 1:1 to either a combination therapy (n = 379) that included 1200 mg of Tecentriq every three weeks plus 160 mg of Xtandi once daily or Xtandi alone (n = 380). No differences were observed in the primary endpoint of overall survival (OS) between the two arms (Median OS, 16.6 months vs. 15.2 months) requiring early termination of the study.

Related Article: AACR 2020 Conference – Advances in the Field of Lung Cancer Targeted Therapies

References

1. https://www.abstractsonline.com/pp8/#!/9045/presentation/10593
2. https://www.abstractsonline.com/pp8/#!/9045/presentation/10594
3. https://www.abstractsonline.com/pp8/#!/9045/presentation/10595
4. https://www.abstractsonline.com/pp8/#!/9045/presentation/10596

Author

Rajaneesh K. Gopinath