Advanced Solid Tumors: New Directions for Checkpoint Blockade
At the 2022 ASCO Annual Meeting, data from clinical trials pointed to an expanding role of immune checkpoint inhibitor (ICI) therapy for several solid tumor types. Clinical trials incorporated ICIs in the adjuvant and neoadjuvant settings, in earlier-stage disease, and in novel combinatorial regimens.
Following these proceedings, featured expert Bruce E. Johnson, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Johnson’s clinical perspectives on key findings are presented here.
“We are seeing confirmation that ICIs play a prominent and critical role in earlier-stage NSCLC. Important studies of neoadjuvant and adjuvant immunotherapies are also being conducted in other solid tumors. . . .”
There were several developments at the 2022 ASCO Annual Meeting that speak to the evidence for immunotherapy agents in the treatment of solid tumors in earlier-stage disease. We are seeing confirmation that ICIs play a prominent and critical role in earlier-stage non–small cell lung cancer (NSCLC). Important studies of neoadjuvant and adjuvant immunotherapies are also being conducted in other solid tumors, including muscle-invasive bladder cancer (abstract TPS4611), resectable stage III melanoma (abstract 9501), and early triple-negative breast cancer (abstract 503). In addition, several studies have involved patients with solid tumors who had progressed after treatment with PD-1 or PD-L1 inhibitors. It was encouraging to see in that setting that by adding an antiangiogenic agent or a multitargeted tyrosine kinase inhibitor to an ICI, you may be able to achieve activity, even in previously ICI-treated patients.
With regard to NSCLC, in May 2022, results from the CheckMate 816 study in patients with resectable disease were published, giving us rather dramatic insights into the effectiveness of neoadjuvant nivolumab plus chemotherapy. Patients with stage IIB and IIIA NSCLC were given nivolumab–plus–platinum-based chemotherapy, which resulted in a significantly longer event-free survival and a higher percentage of patients with a pathological complete response (pCR) compared with chemotherapy alone. The percentages of patients with a pCR were 24% and 2.2%, respectively.
At the recent ASCO meeting, data were presented from the NADIM II trial, which studied nivolumab plus chemotherapy vs chemotherapy alone as neoadjuvant treatment for patients with resectable stage IIIA NSCLC (abstract 8501). In that trial, the rates of pCR (36.2% vs 6.8%) and definitive surgery (91% vs 69%) were higher when nivolumab was added to chemotherapy compared with chemotherapy alone. In both CheckMate 816 and NADIM II, you saw a rather dramatic increase in pCR rates, on the order of 5- to 10-fold, and we have data from randomized trials showing that this correlates with a prolongation of progression-free survival. This has certainly changed the paradigm of treating patients who have locally advanced NSCLC. Notably, there is a greater degree of benefit with ICI therapy in patients with later-stage disease (ie, stage IIIA), although there is still a smaller benefit in those with stage IB or II NSCLC.
Another challenge that is applicable to several different tumor types is related to treating patients whose tumors lack a targetable oncogenic driver in the frontline setting. In NSCLC, most of these patients are treated with chemotherapy plus an ICI, and most eventually progress. Therefore, I often encourage patients to consider participating in a clinical trial. Anti-VEGF agents combined with anti–PD-1/PD-L1 antibodies are regimens of interest in this setting.
In the Lung-MAP nonmatch substudy (S1800A), the combination of ramucirumab plus pembrolizumab was compared with the investigators' choice of standard-of-care options for patients with NSCLC who had progressed on prior ICI therapy (abstract 9004). The results indicated a significant improvement in overall survival for ramucirumab plus pembrolizumab. The combination of cabozantinib plus atezolizumab is another regimen that was reported at ASCO 2022. Cabozantinib is a multitargeted tyrosine kinase inhibitor that is used in a number of different clinical settings, and it is already approved by the US Food and Drug Administration in cancers other than lung cancer. In populations of patients who have progressed on ICIs, trials in solid tumors, including advanced NSCLC (abstract 9005) and urothelial carcinoma (abstract 4504), are assessing cabozantinib plus atezolizumab, and preliminary results are encouraging. It is good to see that adding an antiangiogenic or a multitargeted kinase to an ICI can produce these encouraging results, particularly in those who have had PD-1 or PD-L1 inhibitors and whose tumors have progressed on those therapies.
Ultimately, the idea is to develop a more precise approach to immunotherapy. We do not know whether we will be successful with precision immunotherapy, but we are certainly trying to move in that direction. I am involved with the Human Tumor Atlas Network, which is part of the National Cancer Institute–funded Cancer Moonshot Initiative, and our aims are to define mechanisms of resistance to immunotherapy for melanoma and lung cancer and to develop a means to overcome these mechanisms of resistance.
One of the challenges with immunotherapy currently relates to our predictive markers. Unlike testing for EGFR mutations, which are present or absent, when we are trying to select patients for ICI therapy using predictive biomarkers, we consider the tumor mutational burden, the PD-L1 expression level, and potentially various tumor suppressor mutations. And the likelihood of response does not fall neatly into a 0 or 1 type category. Part of the ICI response is driven by genomics, but another part of it is driven by the different functions of the immune cells.
To me, it is all very hopeful, but I think that we are going to have to do something similar to what we did with targeted therapies. That is, we will need to define which subset(s) of patients will benefit from immunotherapeutic agents other than PD-L1 or PD-1 inhibitors (eg, an anti-LAG or an anti-TIGIT). We need to refine our predictive markers for particular interventions as more and more of these different immune targets are identified and developed.
Blank CU, Reijers ILM, Saw RPM, et al. Survival data of PRADO: a phase 2 study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma [abstract 9501]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
Neal JW, Santoro A, Viteri S, et al. Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): results from cohorts 7 and 20 of the COSMIC-021 study [abstract 9005]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): results from cohorts 3, 4, 5 of the COSMIC-021 study [abstract 4504]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Provencio-Pulla M, Nadal E, Larriba JLG, et al. Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial [abstract 8501]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Pusztai L, Denkert C, O'Shaughnessy J, et al. Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: exploratory analysis from KEYNOTE-522 [abstract 503]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Reckamp KL, Redman MW, Dragnev KH, et al. Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A [abstract 9004]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
Satkunasivam R, Lim K, Teh BS, et al. A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer (RAD VACCINE MIBC) [abstract TPS4611]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
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