By Ted Bosworth
In early stage non-small cell lung cancer (NSCLC), one source of good news at the 2020 World Conference on Lung Cancer (WCLC 2020) was the efficacy of immune checkpoint inhibitor (ICI) as neoadjuvant therapy. In late stage disease, the news was mixed. In a phase 3 trial, the addition of a second ICI in previously untreated stage IV NSCLC did nothing but add toxicity. However, unique oral targeted agents, including the first KRAS inhibitor, are showing sufficient activity to change outcomes for many with advanced disease.
Neoadjuvant Atezolizumab Shrinks Tumors Prior to NSCLC Resection
In resectable, previously untreated stage IB to IIIA NSCLC, 66 (43%) of 155 patients who underwent subsequent pathologic stage evaluation were downsized after two cycles of neoadjuvant atezolizumab, according to results of the LCMC3 trial. Only 29 (19%) were upstaged. A major pathologic response, which was the primary endpoint, was achieved in 21%, and 7% achieved a pathologic complete response.
“The subsequent resection was achieved with a low rate of morbidity,” reported Jay M. Lee, MD, Chief, Division of Thoracic Surgery, University of California, Los Angeles.
Tumor-free (RO) margins were achieved in 92% of those who underwent surgery. After 1.5 years of followup, 79% of those with stage I or II NSCLC and 77% of those with stage III remained in disease-free survival (DFS). The rates of overall survival (OS) at this interval were 91% and 87%, respectively, which compare favorably to historical data.
There were 181 patients initially recruited for this single-arm study. Of the 159 who went onto surgery, 140 (88%) did so within the predefined protocol window of 30 to 50 days after initiating the first dose of atezolizumab. The median time from the end of cycle 2 of atezolizumab and surgery was 22 days.
Of the 14 surgeries (8%) without tumor-free margins at completion, 7 (4%) were R1. The remainder was R2.
Atezolizumab did not appear to complicate surgery, which was minimally invasive in the majority of cases. For example, the length of hospitalization was 7.5 days or about the same as that reported in previous series.
These data confirm that neoadjuvant ICI is feasible, according to Shinichi Toyooka, MD, Director, Department of General Thoracic Surgery, Okayama University Hospital, Japan. Invited as an expert discussant by the International Association for the Study of Lung Cancer (IASLC), which organized this World Conference, Dr. Toyooka advised ICI plus chemotherapy might still be preferable in those with stage III disease and good performance status.
Dual ICI Adds Nothing to Pembrolizumab Alone in Stage IV NSCLC
The hypothesis that adding a second ICI could improve outcomes over a single ICI in patients with stage IV NSCLC was not validated by the randomized KEYNOTE-598 trial. In a study that recruited patients with no prior systemic therapy but a high rate of PD-L1 expression, the addition of ipilimumab, an ICI targeting CTLA-4, plus pembrolizumab, which targets PD-1, did not achieve an advantage over pembrolizumab for any of the major study endpoints.
“The addition of ipilimumab did not improve efficacy but it did increase toxicity in first-line treatment for stage IV NSCLC,” reported Michael Boyer, MBBS, PhD, Chair of Thoracic Oncology, Chris O’Brien Lifehouse, Camperdown, Australia. He added, “This means that pembrolizumab remains the standard of care in this population.”
In this phase 3 study, patients were required to have PD-L1 expression of at least 50% tumor proportion score (TPS). The 568 enrolled patients were randomized to pembrolizumab at a dose of 200 mg every three weeks plus ipilimumab at a dose of 1 mg/kg every six weeks or to the same dose of pembrolizumab plus placebo. The co-primary endpoints were OS and progression-free survival (PFS).
The study was stopped when the lack of difference in the outcomes crossed previously defined boundaries of futility. At 12 months, survival was 63.6% in the patients on two ICIs versus 67.9% for those on pembrolizumab plus placebo. At the interim analysis the hazard ratio (HR) for the combination went the wrong way for OS (HR 1.08; P=0.74) and for PFS (HR 1.06; P=0.72).
“Essentially every adverse events occurred more frequently in the arm that received both ipilimumab and pembrolizumab,” Dr. Boyer reported. Serious treatment-related adverse events (27.7% vs. 13.9%) and discontinuations due to adverse events (19.1% vs. 7.5%) were both higher in the group on the dual ICI.
Dual ICI therapy has shown an advantage over monotherapy in other cancers, such as melanoma, but the IASLC-invited discussant, Yun Fan, MD, PhD, Director of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China, speculated that ipilimumab might be ineffective in tumors with a high rate of PD-L1 tumor expression. Dr. Fan noted that another NSCLC study that enrolled patients with ≥50% TPS also found this dual ICI combination ineffective.
New Uniquely Targeted Oral Therapies Are Exploding the Possibilities in Advanced NSCLC
Led by a first-in-class KRAS inhibitor, the most significant news for the control of advanced NSCLC might be the progress with oral targeted small molecule inhibitors. Based on a phase 2 study, the KRAS inhibitor sotorasib might offer the most immediate promise, but other drugs in earlier stages of development point to increasing individualization of therapy.
By inhibiting KRAS, sotorasib, has reached a target once thought undruggable, according to Bob T. Li, MD, Co-Director of the Thoracic Liquid Biopsy Program, Memorial Sloan Kettering Cancer Center, New York, New York. In advanced KRAS-mutated NSCLC, sotorasib was associated with “deep and durable responses” with little toxicity. He predicted a major role for this agent upon regulatory approval.
In this phase 2 study involving centers in 11 countries, called CodeBreaK 100, 126 previously treated patients with locally advanced or metastatic NSCLC with KRAS G12C mutation were enrolled. About 90% had received either an ICI or a platinum-based chemotherapy. Eighty-one percent had received both. The treatment was oral sotorasib once daily until disease progression.
For the primary endpoint, 34.7% achieved a partial response and 2.4% achieved a complete response. Disease control was observed in 86%, and some degree of tumor shrinkage was achieved in 81%. The median duration of response was 10 months. The median overall PFS was 6.8 months, but 43% remained on therapy without progression at the time of data cutoff, according to Dr. Li.
Diarrhea was the most common adverse event, occurring in 31%, but reached grade 3 severity in only 4%. Except for a blood alkaline phosphatase increase in one patient, the only other grade 3 events, occurring in less than 10% of patients, were liver enzyme elevations.
Due to the importance of KRAS mutations, which is the driver of progression in an estimated 13% of advanced NSCLC, Dean Fennell, MBBS, PhD, Chair of Thoracic Medical Oncology University of Leicester, UK, called these results “fabulous.” In his opinion, it means that characterization of KRAS status will now be an essential step to NSCLC management.
Due to the relative importance of the KRAS mutation, the sotorasib findings were featured in the President’s Symposium, but progress with other currently untreatable drivers of NSCLC suggest major progress in this field. Examples include mobocertinib, which targets epidermal growth factor receptor (EGFR) Exon20 insertions, and tepotinib, which targets MET exon14.
The objective response rate with mobocertinib in 96 patients with advanced EGFR Exon20+ advanced was 28% in a phase 1/2 trial presented by Caicun Zhou, MD, PhD, Director, Department of Oncology, Shanghai Pulmonary Hospital, China. This is impressive because the patients had all been treated previously with platinum-based chemotherapy, and the response was associated with durable disease control.
“The median duration of response was 17.5 months,” according to Dr. Zhou, who characterized this as a meaningful benefit in a group with highly limited treatment options.
In the phase II VISION study of tepotinib for treatment of METexon14 skipping advanced NSCLC, the overall response rate was 45.2%. The median duration of response was 11.1 months, according to Paul K. Paik, MD, Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City.
As in the experiences with sotorasib and mobocertinib, the activity with this highly targeted therapy was consistent across prior treatment experience. In the case of tepotinib, for example, responses were similar regardless of prior exposure to ICI, Dr. Paik reported.
Despite their early stage, these data predict increasing individualization of late stage NSCLC for very specific targets, allowing substantial hope for extending the lives of NSCLC patients with advanced disease regardless of the underlying driver.
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