A Wealth of Therapeutic Advances in Lung Cancer Stress a Need for Early NGS Testing

Stephen V. Liu, MD

The overwhelming number of options for the treatment of patients with lung cancer underscores the importance of broad molecular testing up front to ensure patients receive optimal care, said Stephen V. Liu, MD.

“Our strategies [for managing lung cancer] are becoming more sophisticated and precise, but the first step of broad next-generation sequencing [NGS] is really the key. NGS is essential to make sure we set off on the right path. If we detect a target, we have targeted options in the frontline and salvage settings,” Liu, an associate professor of medicine, director of Thoracic Oncology, and director of Developmental Therapeutics at the Lombardi Comprehensive Cancer Center of Georgetown University, said in an interview with OncLive® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

“If we don’t detect a target that is there, we set off on a wrong path that is dominated by immunotherapy. Giving immunotherapy when a driver is present is largely ineffective, so this is a setting where it is vital to know whether a mutation is present or absent and to act accordingly,” Liu added.

The virtual meeting covered management strategies across the lung cancer paradigm, including stage III non–small cell lung cancer (NSCLC), EGFR- and MET-positive NSCLC, and mesothelioma, as well as the evolving role of frontline immunotherapy in advanced NSCLC.

In the interview, Liu, who chaired the meeting, discussed the role of immunotherapy in locally advanced and advanced NSCLC, the challenges of navigating new targeted options in EGFR- and MET-mutated NSCLC, and the new standard of care for mesothelioma.

OncLive®: How are you incorporating some of these significant advances in the treatment of patients with thoracic malignancies in clinical practice?

Liu: The biggest advances we’ve had in the treatment of [patients with] lung cancer fall into 2 general strategies. Immunotherapy and the induction of immune-mediated antitumor responses offer modest response rates overall, but [has the potential to provide] long-term, durable responses, and potentially even cure, for some patients. 

In parallel, we’ve developed many targeted agents that offer very high response rates. [However,] the benefits are transient, and resistance is something we must anticipate and overcome. We’ve seen these [targeted options] first emerge in the late-stage setting for patients with metastatic NSCLC. More recently, we’ve seen them move into the earlier-stage setting.

During the IPC meeting, Joshua Reuss, MD, of the Georgetown Lombardi Comprehensive Cancer Center, discussed management strategies for patients with stage III NSCLC. What unanswered questions remain with adjuvant and neoadjuvant immunotherapy in this patient population?

Immunotherapy has clearly affected late-stage disease, but now we are starting to see immunotherapy have an effect in an earlier stage. The PACIFIC study [NCT02125461] clearly showed that the addition of consolidative durvalumab [Imfinzi] after definitive chemoradiation significantly improved progression-free survival [PFS] and overall survival [OS] vs placebo. [The PACIFIC regimen] has become our undisputed standard of care for many years, but now we are seeing the same paradigms applied to resectable NSCLC. Immunotherapy offers the potential to improve outcomes for patients with resectable NSCLC, but we are not sure what the best way to use [immunotherapy] is.

CheckMate 816 [NCT02998528] explored a neoadjuvant approach with the addition of nivolumab [Opdivo] to neoadjuvant chemotherapy. By adding the PD-1 inhibitor, we saw a significant increase in the pathologic complete response [pCR] rate, which was 2.2% with chemotherapy alone vs 24% with the addition of nivolumab. This is clearly showing efficacy without any new concerning safety signals. We don’t know whether this will translate to an improvement in event-free survival [EFS] or OS though.

One concern that some of us had was regarding the effect of nivolumab on subsequent surgery. Anecdotal reports have shown that giving immunotherapy before surgery increases peripheral fibrosis, which potentially increases complications with surgery. This year, we saw [data indicating] that this is clearly not the case. Nearly all surgical outcomes were better. We saw that surgeries were shorter and there were fewer conversions [to] open thoracotomy and pneumonectomies, more minimally invasive surgeries, and fewer complications. Overall, the surgeries were better [with nivolumab]. We don’t have a great mark for ease of surgery, but clearly, there wasn’t a higher rate of complications and it seemed to be a safe and hopefully effective approach. We must wait to see how this translates into EFS and OS.

At the same time, we saw adjuvant immunotherapy approaches being explored in the IMpower010 trial [NCT02486718], which is looking at adjuvant atezolizumab [Tecentriq]. This trial enrolled patients with resected NSCLC; patients were randomized after adjuvant chemotherapy to 1 year of adjuvant atezolizumab or best supportive care. The addition of atezolizumab in [patients with] PD-L1–positive resected stage II to III NSCLC significantly improved disease-free survival [DFS], which was the primary end point, with an HR [hazard ratio] of 0.66.

If we look at the PD-L1–high subset with a score of 50% or greater, the HR is even better at 0.43. We don’t know whether this will translate into improved OS, but this is clearly an impressive landmark. In the PD-L1–low group with a score of 1% to 49%, the benefit is understandably a bit lower with an HR of 0.87.

One analysis presented looked at the PD-L1[–positive] cohort but excluded [patients who harbored] EGFR and ALK [mutations], which was a very reasonable thing to do. This is a setting where we probably won’t explore immunotherapy for EGFR[-positive disease] because we have the approach of osimertinib [Tagrisso] in this setting after the ADAURA trial [NCT02511106]. If we look at the EGFR and ALK wild-type setting for [patients with] PD-L1–low NSCLC, the DFS HR is 0.82, which is an improvement. We will have to wait to see whether this affects OS, but it is a step in the right direction. [These data from IMpower010] garnered FDA approval [for adjuvant atezolizumab] in October 2021. 

Narjust Duma, MD, of Dana-Farber Cancer Institute, spoke to treatment options in advanced EGFR-positive NSCLC during the IPC event. What are some factors that must be taken into consideration when it comes sequencing EGFR TKIs in this patient subgroup?

Another area in which we have seen advances is in the EGFR-mutated subset of NSCLC. Our current standard of care for patients with stage IV EGFR-mutant lung cancer remains osimertinib, a third-generation EGFR TKI. This was established from the FLAURA study [NCT02296125], where first-generation TKIs were compared with osimertinib. We saw an improvement in PFS with an HR of 0.46. The median PFS was 18.9 months [with osimertinib] vs 10.2 months [with gefitinib (Iressa) or erlotinib (Tarceva)]. We saw that more follow-up translated into an OS benefit with an HR of 0.80, which made osimertinib our preferred standard of care in the frontline setting for patients with EGFR-mutant NSCLC.

Our focus now is on resistance to osimertinib because although responses are fast and frequent, they are, unfortunately, transient. We think about how cancers can evade osimertinib; histologic transformation does occur, which merits tissue biopsy. We can see small cell transformation, as well as squamous cell transformation. Although we may be clued into that based on patterns and rates of growth, we can be surprised, and I suspect these [transformations] are underreported. It’s now become our standard of care at my institution to pursue tissue biopsy in all cases of osimertinib resistance. We also seek NGS to look for actionable targets mediating resistance to osimertinib. This is often done with liquid biopsy, but also tissue biopsy. We don’t have a dominant mechanism like T790M mediating resistance to first-generation TKIs. We do see C797S mutations, which mediate resistance to osimertinib. First-generation TKIs may retain activity in the presence of that mutation if there is not a concurrent T790M mutation, but we don’t see it in the same proportion as we see C797S mutations. It’s a lot of smaller slices of the pie that we see MET amplifications, RET fusions, BRAF mutations and fusions, KRAS mutations and amplifications, and EGFR amplifications. If we see something actionable, like a RET fusion, then combinations with TKIs are appealing, although the data are somewhat limited regarding safety and optimal dosing. 

The standard of care remains platinum-based chemotherapy with pemetrexed [Alimta]. One question we have to answer is: What do we do with the TKIs in that setting? Do we continue osimertinib knowing that this will increase the cost of the regimen and, to a modest degree, toxicity but provide benefit?

The IMPRESS trial [NCT01544179] looked at this approach with gefitinib, a first-generation TKI. We saw [from those data] that continuing gefitinib at the time of progression with chemotherapy was not beneficial and was potentially detrimental. However, that may not apply to osimertinib because it is a more selective and better tolerated drug. [We’ve seen] some retrospective safety data published in Clinical Lung Cancer [supporting that idea] and there is the ongoing COMPEL study [NCT04765059] looking at the value of continuing osimertinib at the time of progression.

One of the dimensions osimertinib adds is central nervous system efficacy. In patients who have their brain disease controlled by osimertinib, there is value in continuing osimertinib. For patients with brain involvement of their cancer, I routinely continue osimertinib with chemotherapy provided it is better tolerated.

Benjamin Levy, MD, of Johns Hopkins Sidney Kimmel Cancer Center, highlighted the emergence of MET as a targetable alteration in advanced NSCLC. What is known about mechanisms of resistance to MET-directed therapies, and how they can be overcome?

MET, which is an emerging target, is interesting because MET exon 14 skipping mutations [METex14] are clearly actionable for which we have approved and effective targeted agents. However, METex14 mutations also seem to mediate resistance to other drivers and kinase inhibitors. Combinations with MET inhibitors are going to be commonly used in the future.

We now have 2 approved agents for METex14-mutant NSCLC: capmatinib [Tabrecta] and tepotinib [Tepmetko]. Both agents are effective with durable responses and comparable safety profiles. We see some edema and swelling related to targeting MET overall, as well as with both agents. [The edema] generally responds well to dose reductions. 

We need newer agents for METex14-mutant NSCLC. An agent that has shown some interesting activity is amivantamab-vmjw [Rybrevant], a bispecific antibody that targets EGFR and MET. Amivantamab has been approved as a second-line treatment for EGFR exon 20 insertion–mutant NSCLC, but because it also targets MET, it’s been explored in METex14-mutant NSCLC.

In [the METex14-mutated cohort of the CHRYSALIS trial (NCT02609776)], we saw impressive response rates north of 60% [with amivantamab] and comparable safety profiles [to capmatinib and tepotinib]. Amivantamab is a promising drug for METex14-mutant NSCLC. We have active drugs, but it is good to have many active drugs. However, we need to determine the best sequence and whether certain subtypes will respond better to one treatment vs another. That rank-and-file will happen over the next few years, but we can add amivantamab to that as an active agent worthy of further study in this important subset of NSCLC.

Chul Kim, MD, MPH, of the Georgetown Lombardi Comprehensive Cancer Center, discussed updates in the frontline treatment of patients with advanced NSCLC. How are you navigating that landscape given the wealth of therapeutic options available?

The immunotherapy space for stage IV NSCLC is rapidly evolving. We have many options, almost an embarrassment of riches. One of the latest additions to our arsenal from the POSEIDON study [NCT03164616] exemplifies that issue. The trial looked at frontline combination immunotherapy for patients with EGFR/ALK wild-type NSCLC. Patients in the study were randomized to chemotherapy alone, chemotherapy with the PD-L1 inhibitor durvalumab, or chemotherapy with durvalumab and tremelimumab, a CTLA-4 inhibitor, which was given in a limited 5 doses. 

The primary end point showed that the addition of durvalumab to chemotherapy improved PFS; the 1-year PFS rates were improved from 13.1% [with chemotherapy alone] to 24.4% [with the combination] with an HR of 0.74. We saw a trend toward improved survival, but it did not quite reach significance; however, the positive PFS value with durvalumab plus chemotherapy triggered a formal analysis of the durvalumab plus tremelimumab arm.

That combination of durvalumab, a limited number of doses of tremelimumab, and chemotherapy improved PFS with an HR of 0.72 and OS with an HR of 0.77. Those curves split fairly early. We saw that the 2-year OS rate was improved from 22.1% with chemotherapy to 32.9% with [the triplet]. This was the first positive trial for tremelimumab, and it showed impressive results.

We also saw improvements in response rate and duration of response [with the triplet regimen] over chemotherapy with very reassuring safety data. POSEIDON gives us yet another chemoimmunotherapy combination that confers benefit over chemotherapy alone.

We have learned that no patient should receive frontline chemotherapy alone. [They should receive] targeted therapy for oncogenic drivers or some form of immunotherapy if no drivers are present. I’m not sure there is anything compelling enough to change our current [practice], but what the field really needs are biomarkers to help us decide what regimen to use where.

Melina Marmarelis, MD, of the University of Pennsylvania, closed out the IPC meeting by highlighting the current state of mesothelioma management. What is the current standard of care and how has it improved upon historic options in this patient population?

Another area in which immunotherapy is having impact is in mesothelioma. Our long-term standard of care had been platinum-based pemetrexed chemotherapy, which offered modest responses with significant room for improvement. That [improvement] came in the form of CheckMate 743 [NCT02899299], which looked at frontline immunotherapy with the combination of nivolumab given at 3 mg/kg every 3 weeks and ipilimumab [Yervoy] given at 1 mg/kg every 6 weeks vs chemotherapy. Dosing was important because that 1-mg/kg dosing schedule was much better tolerated in thoracic malignancies and was different from what we have seen in other types of cancers.

Nivolumab plus ipilimumab conferred a survival benefit compared with chemotherapy. This was a large study of more than 600 patients. When we broke it down by histology, the benefits were much greater in the non-epithelioid mesothelioma subtype, which is a setting where chemotherapy is largely ineffective. Chemotherapy offered a median survival of 8.8 months compared with 18.1 months with nivolumab plus ipilimumab with an HR of 0.46. The curves split quickly with a dramatic difference. The 2-year survival rates were 8% with chemotherapy and 38% with nivolumab plus ipilimumab. Based on these data for non-epithelioid mesothelioma, nivolumab plus ipilimumab is a clearly superior standard of care vs chemotherapy.

For epithelioid mesothelioma, the benefit was a bit less pronounced with an HR of 0.86, which didn’t quite meet significance. The median survival was 16.5 months with chemotherapy and 18.7 months with nivolumab plus ipilimumab. Interestingly, the median survival with nivolumab plus ipilimumab was similar between epithelioid and non-epithelioid, but the major difference in HR is because chemotherapy performs much worse in the non-epithelioid subtype. Therefore, for epithelioid mesothelioma, the difference is less impressive, but [nivolumab plus ipilimumab] is a very reasonable option for both subtypes.

Future studies are looking at combinations of chemotherapy and immunotherapy, which may be the best approach.