The 2021 ASCO Annual Meeting highlighted innovative lung cancer research findings with both immediate and longer-term clinical practice implications
This year’s ASCO Annual Meeting showcased new findings that I believe can change our practices immediately, with others pointing toward exciting future opportunities. Key lung cancer presentations included:
A new postoperative immunotherapy for non–small cell lung cancerDr. Heather Wakelle of Stanford shared results of the IMpower010 trial,1 which showed the value of adding postoperative immunotherapy with atezolizumab after postoperative (adjuvant) chemotherapy for patients with resected stage 1B to 3A non–small cell lung cancer (NSCLC). Before studying the addition of atezolizumab, we already knew that we could cure some cancer patients with just surgery and more patients by adding chemotherapy.
All trial patients received at least one cycle of chemotherapy, with a target of up to four cycles. Patients were then randomized evenly between atezolizumab year-long immunotherapy and supportive care, which included essential clinical and imaging surveillance. The trial had a complex statistical design focusing on disease-free survival, which is the time before the cancer potentially returns. The trial didn't focus as much on overall survival, which is where we'd ideally like to see improvement. Thus, the question remains whether more patients survive in the years following their cancer diagnosis.
The trial showed an improvement in disease-free survival among patients with stage 2 or 3A disease, with a higher risk of recurrence than in patients with stage 1B disease and tumor PD-L1 expression of 1% or greater. However, the benefit appeared concentrated in the patients with high tumor PD-L1 expression, the approximately one-third of patients with expression over 50%. As we've known for years, this subgroup tends to receive a particularly good prognosis with immunotherapy.
Though the trial didn't demonstrate these aforementioned results in patients with low PD-L1 expression, the subset with high PD-L1 apparently drove the observable benefit in patients with any degree of PD-L1 expression. Patients with stage 1B, 2, or 3A disease with any degree of PD-L1 showed no significant improvement in disease-free survival. Overall, the patients with negative PD-L1 expression apparently didn’t receive any benefit in disease-free survival from the addition of immunotherapy. We also didn’t see any significant improvement in overall survival results, although the trial findings are still preliminary.
Ultimately, I believe this trial will likely lead the Food and Drug Administration (FDA) to approve atezolizumab (Tecentriq®) as a postoperative therapy for a subset of NSCLC patients. I also believe, however, that the benefit is most compelling for patients with high tumor PD-L1 expression and not nearly as compelling for other patients. Up to this point, we haven't seen an improvement in disease-free survival in even a subset of patients translate into any improvement in overall survival.
A preoperative combination of immunotherapy and chemotherapy for improved outcomesDr. Jonathan Spicer of McGill University presented the trial, CheckMate 816, which examined the value of adding immunotherapy to chemotherapy before surgery.2 A bit of background: At an American Association for Cancer Research (AACR) meeting earlier this year, we saw very provocative data on immunotherapy with chemotherapy. The data showed that adding nivolumab (Opdivo®) to three cycles of chemotherapy before surgery for patients with stage 1B to 3A NSCLC greatly improves the probability that viable cancer cells won't appear under the microscope at the time of cancer surgery. The noted improvement was from a 2.2% probability with chemotherapy alone to 24% with nivolumab plus chemotherapy. Further, the trial had previously reported that the probability of the tumor shrinking significantly on imaging from this preoperative treatment went from about 9% with chemotherapy alone to 37% with nivolumab plus chemotherapy.
Dr. Spicer's 2021 ASCO Annual Meeting presentation showed that patients who received nivolumab with chemotherapy underwent surgery that required 30 minutes less time than if they had received chemotherapy alone, without delay in the time to get to surgery. We also saw that more patients who received nivolumab with chemotherapy underwent a minimally invasive surgery that didn't require converting to an open thoracotomy—a more significant surgery for patients to endure. This was particularly true for patients with stage 3A disease, who express ambivalence regarding potentially needing a more significant surgery. More patients who received nivolumab immunotherapy with chemotherapy underwent a lobectomy rather than a pneumonectomy; the latter being a surgery that removes the entire lung instead of just one lobe. The hospital stays of patients who received nivolumab immunotherapy with chemotherapy trended shorter, without an increase in postoperative complication rates.
We did, however, witness a trend toward lower rates of shortness of breath and noncardiac chest pain (NCCP). These lower rates were especially evident for pain in patients who received immunotherapy with chemotherapy, compared to chemotherapy alone—likely because the immunotherapy combined with chemotherapy was associated with less extensive surgery.
Overall, we've observed that adding nivolumab to chemotherapy in a preoperative or neoadjuvant led to many improvements in outcomes, although we still don't have results from postoperative event-free survival or overall survival. Though this approach isn't a standard of care at this time, I believe that we’ll very likely be increasingly integrating immunotherapy into lung cancer treatments in curative settings, which I hope translates to better patient survival.
Chemoimmunotherapy: a stronger choice than immunotherapy alone in patients younger than 75Let's now turn to advanced NSCLC, which is the type of cancer we see in a very large portion of our lung cancer patients. The FDA presented an analysis of results from multiple clinical trials submitted during the last few years that focused on whether immunotherapy alone is comparable to chemoimmunotherapy as a combination for the subset of patients with low tumor PD-L1 expression (1% to 49%).3 This subgroup comprises approximately 40% of our patients, and there are competing standards of care at play. It’s more common for us to give chemotherapy combined with immunotherapy, but there are a couple of alternative FDA-approved options that only include immunotherapy without chemotherapy. Specifically, patients can potentially receive pembrolizumab (Keytruda®) alone or the combination of nivolumab (OPDIVO®) with ipilimumab (Yervoy®). The analysis by FDA investigators showed that the median progression-free survival (PFS) was 4.2 months for those who received immunotherapy alone, compared to 7.7 months for those who received chemoimmunotherapy; yet, there wasn’t a notable difference in patients 75 years and older. These results support what many of us have already assumed—that chemoimmunotherapy is likely a superior choice for most patients, but immunotherapy alone may do just as well for older and/or frailer patients.
Novel treatment options for lung cancer patients with an epidermal growth factor receptor mutation
I also discovered studies that examined treatment options for patients whose tumors harbor an epidermal growth factor receptor (EGFR) mutation and whose cancer had progressed on prior EGFR inhibitor therapy; most commonly osimertinib (Tagrisso®). While Tagrisso works very well for most patients with an EGFR mutation-positive NSCLC, it isn't permanently effective. We also don't clearly know what to do after the cancer begins to progress with acquired resistance.
One study looked at the combination of amivantamab (Rybrevant™), which is a bispecific antibody that targets both EGFR and another target, MET, that can be abnormal in this setting, combined with another oral EGFR inhibitor, lazertinib.4 This combination showed an overall 36% response rate (significant tumor shrinkage), and it's now being studied further both in patients whose cancer has already progressed on Tagrisso and as a first-line treatment possibly superior to Tagrisso or lazertinib alone in previously untreated patients with an EGFR mutation-positive NSCLC.
Another study in this EGFR mutation-positive cancer population that has acquired resistance looked at an antibody-drug conjugate (ADC) linking chemotherapy with an antibody to the target HER3,5 which is in the same family as the EGFR target. This ADC was associated with a 39% response in previously treated patients.
Newly approved therapy against KRAS, a longtime evasive target
I also learned of a study on the recently FDA-approved therapy sotorasib (Lumakras™) to treat NSCLC that harbors a KRAS G12C mutation,6 which is seen in about 13% of advanced lung cancers. This oral agent was studied in patients who had received both chemotherapy and prior immunotherapy, and the response rate was 37% in this significantly pretreated population, with the median overall survival being just over a year in this group, despite the significant prior treatment. In addition, many ongoing studies are looking at the best way to integrate this oral agent into current clinical practice, e.g., how to use it as an initial rather than a later treatment for patients with advanced NSCLC that harbors a KRAS G12C mutation.
The need for more-reliable molecular marker testing in advanced lung cancer
Two additional studies focused on the rates that patients with advanced NSCLC are tested for molecular markers, which is the current standard of care to determine if targeted therapy or immunotherapy will be the best treatment option.
One study by The US Oncology Network looked at molecular testing patterns in approximately 3,500 patients with advanced NSCLC.7 The study found that less than half of the patients had undergone testing for all five of the markers in current clinical guidelines with approved treatments. The rates of next-generation sequencing (NGS)—which is the increasingly preferred broad molecular testing option for potentially relevant molecular markers—improved from 33% to 45% over a two-year period (April 2018 through March 2020), which is a relatively disappointing result.
Overall, these findings highlight the need to continue looking at and trying to overcome barriers to broad molecular testing. An ever-increasing array of good treatment options exist based on these markers, but the markers will only benefit patients if we continue to identify and follow up on them.
Another study corroborated that less than 50% of patients had undergone molecular marker testing according to the Flatiron database, also noting that Black patients had significantly lower rates of molecular testing and participation in clinical trials with novel treatment approaches.8 This finding underscores the need to address cancer health disparities with molecular testing to help ensure better health equity.
Overall, the meeting represented an exciting year that clearly moved the field forward in lung cancer, with great promise for future directions and better patient outcomes.
Authored by Dr. Jack West.
Last medically reviewed July 21, 2021
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