Experts Chip Away at Resistance, Sequencing, and Targeted Therapy Selection in Lung Cancer

Edgardo Santos, MD, FACP

The integration of osimertinib (Tagrisso) into the adjuvant and first- and second-line settings has transformed the treatment paradigms for patients with EGFR-mutated non–small cell lung cancer (NSCLC), including those with brain metastases, said Edgardo Santos, MD. To continue to transform the paradigm researchers are developing and optimizing therapeutic approaches for patients following progression on the third-generation tyrosine kinase inhibitor (TKI).

“Osimertinib brought a new paradigm to the adjuvant setting [of NSCLC],” said Santos, a clinical affiliate associate professor at the Charles E. Schmidt College of Medicine of Florida Atlantic University and founding partner of Florida Precision Oncology, in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on lung cancer. “[However, resistance is] the problem we have; we need to understand that the mechanism or pattern of resistance for osimertinib is different when we use [the agent] in different settings.”

The virtual meeting covered targeted approaches for patients with EGFR- and ALK­-positive NSCLC, frontline immunotherapeutic options in NSCLC, management strategies for patients with stage III disease, and how the field of small cell lung cancer (SCLC) is navigating newly available therapies.

In the interview, Santos, discussed the current state of targeted therapies for EGFR- and ALK-positive NSCLC, as well as immunotherapy in stage III NSCLC, and management strategies in SCLC.

OncLive^®: During the IPC meeting, your presentation focused on targeting EGFR mutations in the adjuvant and advanced NSCLC settings. How has osimertinib emerged as a standard adjuvant treatment for patients?

Santos: The data [regarding] adjuvant [treatment] for EGFR[-mutant NSCLC] came from the ADAURA trial [NCT02511106], a large phase 3 trial in which patients with early-stage nonsquamous, EGFR exon 19– or exon 21 L858R–mutated NSCLC were treated after surgery. [Patients could have received] chemotherapy or not by the discretion of their physician. Patients were randomized to osimertinib, a third-generation TKI, for 3 years vs placebo.

The primary end point was disease-free survival [DFS] for those patients who had stage II or stage IIIA NSCLC after surgery. The secondary end point was DFS for patients with stage IB, IIA, and IIIA NSCLC.

The [results of ADAURA] were positive. Because of that, the study was stopped and, later, the FDA approved osimertinib for these patients based on [the] DFS [data]. Osimertinib demonstrated a very impressive HR of 0.17, which [translated to] an 83% [improvement] in DFS. When we look at the group that included patients with stage IB, II, and IIIA NSCLC, the HR for DFS was 0.21, which was still an excellent result.

Moreover, we also saw the data of central nervous system [CNS] protection because we know osimertinib crosses the blood-brain barrier. We saw that the incidence of CNS [metastases] in patients receiving osimertinib was significantly lower compared with those patients who received placebo.

Patients who undergo lung cancer resection must be tested for EGFR mutations because if the patient is positive [for EGFR], they can receive standard systemic chemotherapy, depending on the decision between the clinician and the patient, and proceed to osimertinib at a standard dose of 80 mg once daily for 3 years.

Regarding the second part of your presentation on resistance in EGFR-mutated NSCLC, how did the data from the phase 3 FLAURA trial (NCT02296125) set the stage to evaluate resistance mechanisms in this space?

To provide some background, osimertinib is a category 1 [recommendation] by the National Comprehensive Cancer Network for patients who have EGFR-mutated NSCLC. This approval came from a landmark study called FLAURA. [The results were] initially presented for the primary end point of progression-free survival [PFS]. At that time, the highest PFS that we had for monotherapy was 18.9 months for the intention-to-treat population. The FDA and other regulatory entities worldwide approved first-line osimertinib for use in that specific scenario.

The toxicity profile with osimertinib was better than those of second- and third-generation TKIs, such as afatinib [Gilotrif], dacomitinib [Vizimpro], gefitinib [Iressa], and erlotinib [Tarceva]. Because of the toxicity profile plus the PFS [benefit], we adopted osimertinib as a preferred agent in this space. Later, the [results of the] FLAURA study were able to show an overall survival [(OS) benefit with osimertinib].

The FLAURA trial was a phase 3 trial in which patients with EGFR exon 19– or exon 21 L858R–mutated NSCLC were randomized to osimertinib vs erlotinib or gefitinib. As I mentioned, the study was positive for PFS and OS.

What research is being done to determine optimal management for patients who progress after osimertinib?

We are developing combinations to rescue patients after progression on osimertinib. At this moment, a lot of us are using the data from the IMpower150 study [NCT02366143], in which patients with EGFR sensitizing mutations received a quadruplet of atezolizumab [Tecentriq], bevacizumab [Avastin], carboplatin, and paclitaxel [vs atezolizumab, carboplatin, and paclitaxel; and vs bevacizumab, carboplatin, and paclitaxel]. That quadruplet was approved by the FDA based on [the survival advantage demonstrated over both triplets].

However, when a patient is receiving targeted therapy, such as osimertinib, it is important to analyze the mechanism of resistance. If we can target another resistance mechanism, we would prefer to use targeted therapy [vs the quadruplet regimen].

Recently, a combination [has emerged] using a dual monoclonal antibody called amivantamab-vmjw [Rybrevant]. Amivantamab is a bispecific dual antibody that has 2 patterns: one attacks EGFR and the other attacks MET. Amivantamab has been combined with lazertinib, another third-generation TKI, which, as a monotherapy, has been shown to be effective against EGFR sensitizing mutations. [Lazertinib has also been effective against] EGFR T709M mutations, which give resistance to osimertinib, and other EGFR mutations. By combining amivantamab with lazertinib in the CHRYSALIS trial [NCT02609776], we have shown a very good overall response rate [ORR] and disease control rate [DCR] for patients who have failed prior osimertinib.

Also in that space, we are looking at the [antibody-drug] conjugate called patritumab [deruxtecan], in which a specific dose of 5.6 mg/kg has been studied in patients who have failed osimertinib. In this regard, patritumab [deruxtecan] has shown [a favorable] ORR and DCR. The study is continuing to develop.

We are moving forward possible scenarios after osimertinib resistance. Moreover, we understand that in patients who have been exposed to osimertinib, one of the mechanisms of resistance that will happen when we use [osimertinib] up-front is the appearance of fusion proteins, such as RET, ALK, and others. It is important that when a patient progresses on first-line osimertinib, our clinicians restage the patients from a molecular standpoint to try to identify the mechanism of resistance. This can be done by liquid biopsy. If [the liquid biopsy] is positive, we can proceed with therapy. If the liquid biopsy, which is basically a blood sample we [use to] study next-generation sequencing [NGS] at progression, is not helpful, we need to do a tissue biopsy, if patients have an accessible lesion.

My other recommendation is to use a platform in which the NGS also investigates RNA. We have these platforms of NGS that [evaluate] DNA and RNA. By doing that, it is very difficult for a fusion protein to escape from our investigation.

During the IPC meeting, your co-chair Luis E. Raez, MD, FACP, FCCP, of Memorial Cancer Institute, discussed the current state of frontline immunotherapy in NSCLC. What points should be noted from his presentation?

Raez gave a wonderful summary of where we are at in NSCLC using immunotherapy with PD-1/PD-L1 inhibitors. He went through the gamut of all [available] monotherapies and combination chemoimmunotherapies.

Raez highlighted novel agents, such as cemiplimab-rwlc [Libtayo], as well as new data presented about a combination of chemoimmunotherapy. We are looking into biomarkers that can tell us which patients may not respond to immunotherapy and what patients may respond to chemotherapy. Some of these biomarkers are STK11, alkB1, KEAP1, and MDM2. More studies are ongoing.

Sotorasib [Lumakras] is approved by the FDA for patients with KRAS G12C mutations, and [another KRAS G12C inhibitor, adagrasib, is in development].

What is the importance of this? We now have targeted therapies for those patients who have KRAS G12C mutations. For more than 30 years, we believed we couldn’t target [KRAS mutations], but now it is a reality. We found, in an analysis of KEYNOTE-042 [NCT02220894], that patients with KRAS mutations seem to do well with immunotherapy. Data showed that coexpression of KRAS and STK11 gives the patient a chance to respond well to immunotherapy despite the presence of these biomarkers. The new concept for immunotherapy and targeted therapy is that we need to pay attention to co-mutations because they will be critical to assess what kind of therapy we need to deliver to our patient.

Also with immunotherapy, the IMpower010 trial [NCT02486718] was amazing because it used immunotherapy with atezolizumab in the adjuvant setting. We just talked about the use of osimertinib in the adjuvant setting. Now, [adjuvant immunotherapy] is a reality and [atezolizumab] became the first FDA-approved immunotherapy in the adjuvant setting. IMpower010 was a large clinical trial in which patients with NSCLC went for surgery and standard adjuvant chemotherapy, and they were randomized to adjuvant atezolizumab for 1 year vs placebo. The study was positive for DFS, and the data were presented to the FDA. [Adjuvant atezolizumab] was recently approved, so now we have 2 ways to approach any patient with lung cancer in the adjuvant setting.

In talking about adjuvant immunotherapy, the patient must have PD-L1 expression above 1% and patients cannot have a driver mutation, such as EGFR or ALK. From IMpower010, we now have something to offer to a lot of patients in this space.

Janakiraman Subramanian, MD, of Saint Luke’s Cancer Specialists, discussed current management strategies in stage III NSCLC. What has been learned from the phase 3 PACIFIC trial (NCT02125461) with durvalumab (Imfinzi), and are there questions that remain?

The PACIFIC trial was a landmark study that [gave us] the [current] standard of care for patients with stage IIIA, IIIB, or IIIC disease who cannot undergo resection. In the PACIFIC trial, patients were treated with concurrent chemoradiation. Patients received at least 2 cycles of chemotherapy and conventional radiation therapy for this scenario. Then, patients were randomized to receive durvalumab every 2 weeks for 1 year vs placebo. This study met its end point of PFS, and later OS. The PFS was 3 times higher [with durvalumab] vs placebo, approximately 17 months. The median OS was close to 48 months, which is great because the prior median OS in this space was between 20 and 29 months.

This has completely changed the paradigm for patients with stage III NSCLC, both adenocarcinoma and squamous cell carcinoma histologies.

We still have problems, though, so what is next? In the PACIFIC trial, only 42% of patients were able to complete a 12-month period of treatment. How can we minimize toxicity after chemoradiation? Also, we lack good biomarkers to select which patients will do better on this sequential treatment. We also don’t know what happens when a patient has a driver mutation, such as EGFR or ALK. What do we do with these patients? Should they be treated with the PACIFIC regimen? We need [answers to these questions] in thoracic oncology.

George R. Simon, MD, FACP, FCC, of Moffitt Cancer Center, discussed best practices for navigating among the available ALK inhibitors in ALK-positive NSCLC. How are you selecting between them?

We have potent medications that can give us tremendous responses and prolongation of PFS. Those agents are brigatinib [Alunbrig], alectinib [Alecensa], and lorlatinib [Lorbrena]. Simon dissected the data of the ALTA-1L [NCT02737501], ALEX [NCT02075840], and CROWN [NCT03052608] trials.

Alectinib has been used for years. We saw impressive results of the 5-year OS rate of around 62%. That is something that we have never seen in this space.

The [most recent] approval was lorlatinib, which [elicited] a very impressive HR and an extremely high ORR. However, what really impacted me was the CNS control. This third-generation ALK inhibitor induced an ORR in patients with brain metastases of 82%. Of those patients, 71% had a complete remission, so there is no question that we are making tremendous progress here.

The question is: How do we sequence these agents? In the ALK space, we [absolutely] need to figure out mechanisms of resistance so the appropriate sequence of ALK inhibitors can be determined.

Simon also mentioned a phase 2 trial [NCT03786692] for this patient [population], which is combining carboplatin, pemetrexed [Alimta], bevacizumab, and atezolizumab. In the past, when you needed to rescue patients with ALK-mutated NSCLC we used [what we learned from] the IMpower150 study. The problem here is that we know pemetrexed for adenocarcinoma and patients with ALK-mutated disease is a very good agent. Plus, in terms of systemic therapy and toxicity, [pemetrexed] is very tolerable compared with paclitaxel. There is a lot of hope in this stage and more coming.

Finally, Alberto Chiappori, MD, of Moffitt Cancer Center, discussed current approaches to treating patients with SCLC. How is the field of SCLC utilizing the novel agents that have been introduced into the paradigm?

The standard of care for patients with extensive-stage SCLC is immunotherapy plus chemotherapy. The CASPIAN trial [NCT03043872] was a landmark trial done in SCLC [that evaluated] durvalumab combined with cisplatin or carboplatin and etoposide. Chiappori also discussed other ways to target SCLC, such as with lurbinectedin [Zepzelca], which was approved by the FDA.

We have seen a new agent emerge that is approved for patients with SCLC who received a platinum-based doublet plus etoposide with or without immunotherapy or topotecan as a second- or third-line agent. What is that? It is a myeloprotective agent called trilaciclib [Cosela]. Trilaciclib is a CDK4/6 oral inhibitor that has a short half-life and is myeloprotective. We give [trilaciclib] to a patient on days they receive chemotherapy. We give it 4 hours prior to the start of the [chemotherapy] infusion.

Trilaciclib addresses the hematopoietic stem cells in the bone marrow so that they are not affected by chemotherapy. [The cells] are arrested in the G1 phase and don’t translate into the synthesis where they are more vulnerable to the effects of chemotherapy. [Trilaciclib] is the only myeloprotective agent that we have in oncology. It [allows for] proactive avoidance of myelosuppression.

Other agents, such as granulocyte colony-stimulating factor agents, are used as a reaction [to myelosuppression] once the damage has been done. For example, a patient who receives chemotherapy may receive those agents. Sometimes we have to wait until a patient becomes neutropenic to apply those medications. In the case of trilaciclib, it is [proactively given].

Something that struck me [during Chiappori’s presentation] was that we are talking about molecular subtypes of SCLC. This is the way in which we will make progress in this disease, which is lacking more effective agents. We are trying to beat this disease by applying molecular analysis to SCLC to talk about different subtypes of disease. By doing that, we discover potential biomarkers, such as JAK1, which have caught the attention of researchers.