David Spigel, MD, chief scientific officer, director, the Lung Cancer Research Program, principal investigator, Sarah Cannon Research Institute, discusses potential upcoming developments in targeted therapies for non–small cell lung cancer (NSCLC).

Targeted therapies against HER2 and TROP2 have produced recent intriguing data, which could lead to accelerated approval strategies in NSCLC, Spigel says. By the end of 2022, multiple antibody-drug conjugates could become FDA approved for the HER2 and TROP2 populations, depending on the results of ongoing phase 3 trials, Spigel explains.

Over the next few years, data will also mature and read out on several clinical trials involving immunotherapy agents in the neoadjuvant and adjuvant settings, which could also shift the treatment paradigm, Spigel concludes.

Videos

David Spigel, MD, discusses potential upcoming developments in targeted therapies for non–small cell lung cancer.


Dr. Spigel on Potential Advancements in Targeted Therapy in NSCLC

Roy S. Herbst, MD, PhD, ensign professor of medicine (medical oncology), professor of pharmacology, Yale School of Medicine, director, the Center for Thoracic Cancers, chief, Medical Oncology, associate cancer center director, Translational Science, Yale Cancer Center, Smilow Cancer Hospital, discusses the evolving treatment landscape of targeted therapies in non–small cell lung cancer (NSCLC).

Multiple FDA approvals highlighted a busy year of action in the lung cancer space in 2021, Herbst says. The approval of osimertinib (Tagrisso) brought targeted therapy to the adjuvant setting for patients with stage I, II, and III NSCLC harboring 

 mutations, Herbst explains. Moreover, the atezolizumab (Tecentriq) was approved for adjuvant treatment in patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on 1% or more of tumor cells, Herbst adds.

These approvals have helped bring some of the best drugs and targeted therapies into earlier settings, Herbst continues. The approval of new targeted therapies, such as amivantamab-vmjw (Rybrevant) as the first treatment for adult patients with NSCLC harboring 

 exon 20 insertion mutations, also demonstrate how the landscape has shifted, Hebst concludes.

Roy S. Herbst, MD, PhD, discusses the evolving treatment landscape of targeted therapies in non–small cell lung cancer.


Dr. Herbst on the Evolution of Targeted Therapies in NSCLC

Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Perelman School of Medicine, University of Pennsylvania, discusses the optimal use of next-generation sequencing in molecular testing in non­–small cell lung cancer (NSCLC).

Though tissue-based NGS remains the standard for molecular testing in NSCLC, tumors can now be sequenced through the minimally invasive plasma-based NGS, Aggarwal says. By utilizing both tissue-based and liquid-based NGS approaches, physicians can gain more from the testing, Aggarwal explains.

All patients with stage IV NSCLC, particularly those with a nonsquamous histology, must undergo NGS molecular testing, Aggarwal concludes.

Charu Aggarwal, MD, MPH, discusses the optimal use of next-generation sequencing in molecular testing in non­–small cell lung cancer.


Dr. Aggarwal on NGS in Molecular Testing in NSCLC

Molecular testing is a critical component of care for patients with non–small cell lung cancer (NSCLC), according to Charu Aggarwal, MD, MPH, who added that novel combination strategies are under exploration for those whose tumors harbor actionable alterations and the role of PD-L1 expression has become more pronounced in that this marker is being utilized to guide clinical decisions irrespective of mutational status.

“Molecular testing in NSCLC is of paramount importance,” Aggarwal said. “Not only do we need to test for actionable mutations, but we also need to test for PD-L1 expression.”

, Aggarwal, the Leslye M. Heisler associate professor for Lung Cancer Excellence at the University of Pennsylvania, shared how to navigate the nuances of molecular testing in non–small cell lung cancer, key developments made in the treatment of those whose tumors harbor actionable mutations, and the role of PD-L1 expression in informing clinical decisions.

: How is PD-L1 expression being used to guide treatment selection in the presence and absence of other molecular markers for patients with NSCLC?

: Unlike other cancers, [PD-L1 status] still helps us decide which patients can receive immunotherapy alone vs those who should receive a combination of chemotherapy and immunotherapy. As such, this is a very relevant marker, and something that we must look at.

I often use [PD-L1 expression] in the setting of a [patient with a] wild-type genotype in case there is no actionable mutation. Additionally, I look at the level [of expression], whether it is negative, 1% to 49%, or greater than 50%, to make a treatment selection.

What are some of the nuances of molecular testing?

The gold standard for molecular testing is tissue-based, next-generation sequencing [NGS]. However, we must not forget that we now have a minimally invasive way to sequence tumors, using plasma-based NGS. We do know that complementary sequencing, using both liquid- and tissue-based NGS approaches, can give us a better yield. We can also use concurrent approaches.

We need to remember that this is a quality measure; this [testing] is something that everyone with a diagnosis of stage IV NSCLC—especially those with nonsquamous histology—must undergo.

Do you foresee the utilization of single-agent targeted therapies evolving to novel combination strategies, for example, in those with 

-mutant NSCLC is [evolving] very rapidly. Although we are used to using single-agent osimertinib [Tagrisso], and we know that it is associated with a survival benefit, in the future, we will be able to build upon [the efficacy achieved with] this therapy [by pairing it] with other novel agents. Hopefully, [by doing this,] we can delay progression, as well as improve survival [in our patients].

How do you foresee the data with co-occurring mutations playing out? Could this information be compelling enough to drive treatment decisions, for example, in those with 

The data with co-occurring mutations are still evolving. We do know that [patients with] genomically complex tumors tend to experience a worse outcome, be it in terms of progression-free survival [PFS] or overall survival [OS]. New data are also [shedding light on] how novel TKIs may [be leveraged] in the presence or absence of 

 mutations. We need larger numbers; I want to wait for larger studies to read out before we start [applying] that to clinical practice.

Should repeat testing be routine in a patient who progresses on frontline therapy?

This is a question that I am asked very frequently. Should routine testing or sequencing be performed in the case of disease progression? This should be the case for patients who are currently on a targeted therapy. However, if they are not on a targeted therapy, and we have already established that they do not have an actionable mutation, it is probably not a worthwhile exercise.

What are some of the data that have been reported with anti-TIGIT agents?

Anti-TIGIT [monoclonal] antibodies are very interesting, and we look forward to [seeing] new data that will be emerging [in this space]. We have already seen preliminary data [with these agents] in patients with high PD-L1–expressing NSCLCs who do not harbor an actionable mutation. Using an anti-TIGIT antibody in combination with a PD-1 agent may increase response rates [in these patients]. How this [approach] will play out in terms of PFS and OS [benefit] remains to be seen.

Articles

Charu Aggarwal, MD, MPH, shares how to navigate the nuances of molecular testing in non–small cell lung cancer, key developments made in the treatment of those whose tumors harbor actionable mutations, and the role of PD-L1 expression in informing clinical decisions.

Navigating the Nuances of Molecular Testing in NSCLC

The shift away from accepting only positive overall survival (OS) data from phase 3 trials as the pathway toward regulatory approval has been the biggest takeaway from 2021 in lung cancer, explained David Spigel, MD, citing the approvals of sotorasib (Lumakras), amivantamab-vmjw (Rybrevant), and mobocertinib (Ekivity), which were all based on phase 1/2 trials. 

“My take on 2021 from a regulatory perspective is this collaboration and willingness to get drugs out there in these settings where we haven’t had great strategies based on early data sets [instead of] waiting for randomized phase 3 trials to be finished in the case of sotorasib, amivantamab, and mobocertinib even though those studies are being done. [What we’ve seen is that we’re instead able to] get drugs out there based on promising early data, which has been great,” said Spigel.

®, Spigel, chief scientific officer and director of the Lung Cancer Research Program and principal investigator at Sarah Cannon Research Institute, provided his perspective on the biggest takeaways from 2021 in lung cancer.

: Based on the number of accelerated approvals over the past year, do you think the field has become more accepting of end points other than OS?

: The big stories for me would be the adjuvant approval of atezolizumab [Tecentriq] in early-stage disease, the accelerated approval of sotorasib in 

 G12C–mutant disease, and the accelerated approval of 2 [

] exon 20 insertion therapeutics: amivantamab and mobocertinib. It’s somewhat controversial, but we’re getting used to the idea that drugs could get approved based on shorter-term outcomes or end points like disease-free survival [DFS] instead of waiting for OS.

I know that’s been a sticking point with a lot of people about adjuvant osimertinib [Tagrisso] use from the ADAURA trial [NCT02511106], in which the approval was based on DFS end points not OS. As I mentioned, now atezolizumab is approved based on a DFS end point. We’ll have to see if OS matures enough to prove positive for both those examples, but even if it didn’t: Is that a reason these drugs shouldn’t be available? In the case of osimertinib appearing to reduce the occurrence of CNS [central nervous system] metastases: Is that not a meaningful end point? Do we have to expect OS improvement? That will be stuff for us to debate in the years to come, but this is probably the biggest take-home for 2021 in terms of regulatory perspectives.

What is your expectation for research in 2022 with regard to targeted therapy?

There’s a lot of work is looking at the role of antibody-drug conjugates [ADCs], which are showing early promise in a variety of tumor settings. These are drugs that target different areas in tumors. TROP2, CEACAM5, HER3, HER2, and B7H3 are targets that are expressed at various levels. There are a lot of targets out there. The biggest data recently have been in HER2 targeting and some of the early data against TROP2 have been exciting in leading to potential accelerated approval strategies in non–small cell lung cancer [NSCLC]. It wouldn’t surprise me if in 2022, we have 2 ADCs approved in the HER2 population and in the TROP2 population with phase 3 trials in progress.

In the next 1 to 3 years, there’s going to be a slew of neoadjuvant and adjuvant immunotherapy studies maturing that will be exciting to think about how to incorporate hopefully positive results into our standard treatment paradigm. There’s still some work to do in the post-osimertinib setting [to see] whether drugs like amivamtamab could play a role, or new agents altogether, but a lot of exciting things are happening in NSCLC.

In small cell lung cancer [SCLC], we had no big stories in 2021 other than lurbinectedin [Zepzelca], which was approved in 2020. We saw a negative phase 3 study with lurbinectedin vs topotecan or cyclophosphamide, doxorubicin and vincristine, but it was a lower dose of lurbinectedin combined with doxorubicin. I don’t think lurbinectedin is going to get withdrawn from the market, but the bar is still somewhat low to get another agent out there in 2022 or beyond. That might be an ADC, or it might be a bispecific antibody. It might even be another cytotoxic like liposomal irinotecan.

There’s been some exciting, early work with immunotherapy in limited-stage SCLC that’s in development. There’s a lot of work to do, and a lot of exciting things are on the horizon. Perhaps now that we’re getting back to in-person meetings, we’ll be able to have more conversations about how to how to best study these agents and hopefully get them approved quicker.

What advice would you give to oncologists to be able to stay abreast of all these advances?

We have so many brilliant providers across our network, and certainly outside of our network. I continue to think about the challenge of keeping up with all this and being so sophisticated with things like gastric cancer, esophageal cancer, breast cancer, and not to mention hematologic malignancies. There’s a lot happening.

There’s a lot of resources out there, whether it’s one on one conversations or emailing or texting, or great resources like the National Comprehensive Cancer Network, ASCO, and AACR. Keeping up with the data is challenging but know that there’s a lot of resources out there and that it’s going to get hopefully easier as we start to better understand how to communicate guidance through results from NGS [next-generation sequencing] testing, or through pathways, or through education seminars. Whether through Zoom or in person, help is present and is going to get better for everybody. I recognize the challenge of keeping up with things and know that there’s a lot of good opportunities for our patients, and we’re going to help everybody understand what those are.

The shift away from accepting only positive overall survival (OS) data from phase 3 trials as the pathway toward regulatory approval has been the biggest takeaway from 2021 in lung cancer.

Shifting Regulatory Approval Pathway Is a Top Takeaway of 2021 in Lung Cancer 

The FDA approvals of several targeted therapies, such as sotorasib (Lumakras), amivantamab-vmjw (Rybrevant), and mobocertinib (Exkivity), as well as immunotherapeutic strategies, such as adjuvant atezolizumab (Tecentriq), represent significant advances made in 2021 for the treatment of patients with non–small cell lung cancer (NSCLC), said Roy S. Herbst, MD, PhD, who added that with these developments, targeting resistance to EGFR inhibitors will be a key research focus in 2022.

“In 2021, the [COVID-19] pandemic continued but lung cancer research improved,” said Herbst, the Ensign professor of medicine (medical oncology) and a professor of pharmacology at Yale School of Medicine, as well as the director of the Center for Thoracic Cancers and chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital. “We are moving in a direction to bring our best drugs, whether they be targeted therapy or immunotherapy, earlier. That stood out to me as a major accomplishment this year.”

,Herbst, who is also the associate cancer center director for Translational Science at Yale Cancer Center, highlighted some of the most significant developments made during 2021 in lung cancer and discussed where he believes research is headed in 2022.

: What advances stand out regarding lung cancer management when you look back on 2021?

: 2021 was the year of adjuvant therapy. At the end of 2020, we had the approval of osimertinib [Tagrisso], which brought targeted therapy to the adjuvant setting [for patients with] 

-mutant, stage I, II, and III lung cancers.

Toward the end of 2021, we had the approval of adjuvant atezolizumab for [patients with] PD-L1–positive stage II and IIIa disease.

Also, [we saw] the approval of a host of new targeted therapies [directed against 

How did some of the regulatory decisions change the scope of treatment for patients with lung cancer this year?

The fact that [sotorasib] was approved in the accelerated approval pathway was historic [because] we have been working to try to target 

 for years. Now we finally have something [against 

Of course, the approval of atezolizumab as adjuvant therapy, as well as the approvals of [amivantamab and mobocertinib] for patients with 

 exon 20 insertions were great advances.

What trials evaluating targeted therapies will be important to keep an eye on in 2022?

As we move forward, from a targeted therapy point of view, the things to keep an eye on right now might be some of the trials for 

 resistance with some of the newer drugs like amivantamab plus lazertinib [NCT04965090]. Some of the phase 3 studies will be important as they move forward.

Looking at ways to target osimertinib resistance will be important. We are also going to be looking at trials [attempting to overcome] resistance to immunotherapy.

Findings from the DESTINY-Lung01 trial (NCT03505710) demonstrated robust and durable antitumor activity with fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with 

-mutant NSCLC. What is next for this drug and targeting 

 is not that [common] among patients [with NSCLC]; a small percentage of patients have 

-mutated disease. However, many more have 

 amplification. The fact that we can use an armed antibody-drug conjugate [ADC] is important.

There is also a HER3-directed ADC that is showing some activity in [patients with lung cancer who develop] 

2021 was probably the year of the ADCs, as well, [directed toward] TROP2, HER2, and HER3. We will see more of that in the years to come.

What questions regarding immunotherapy were answered in 2021, and what do you anticipate the focus of immunotherapy research will be in 2022?

This year, there weren’t that many new studies, but we saw some consolidation and long-term data showing that there is a tail of the curve [with immunotherapy]. We learned that immunotherapy can probably cure patients with metastatic disease in the first-line or refractory settings. However, the other 70% to 80% of patients are not cured [with immunotherapy], so we need to figure out what we are going to do with those patients. What drugs can we use? How do we identify who needs combination therapy?

We didn’t have that much new [data] this year as far as what those combination [strategies] are. There were some hints from a trial called COAST [NCT03822351] that looked at patients post-chemoradiation with durvalumab [Imfinzi] compared with durvalumab plus a natural killer agonist or CD73 antagonist. [The data] showed some response rate and progression-free survival improvement. That was a signal-finding [study] to move [the field] forward. It was a positive result this year. However, the COAST trial was a phase 2 study, so we have a long way to go.

We also presented the 5-year data from the KEYNOTE-010 trial [NCT01905657], which certainly showed a nice tail of the curve [with pembrolizumab (Keytruda)].

We are developing a lot of signal-finding studies with immunotherapy. TIGIT is one that is high on the list, for example. Now, we need to figure out how to bring these [drugs] forward in a more accelerated way.

What areas of research would you like to see focused on in 2022?

I would like to see immune resistance targeted more. [For patients with] primary resistance who don’t respond to immunotherapy or chemoimmunotherapy, I want to understand why [they develop resistance] and give them different combinations. For patients with acquired resistance to immunotherapy, what do we do there? That is going to be important.

The FDA approvals of several targeted therapies, such as sotorasib, amivantamab-vmjw, and mobocertinib, as well as immunotherapeutic strategies, such as adjuvant atezolizumab, represent significant advances made in 2021 for the treatment of patients with non–small cell lung cancer.

FDA Approvals Signify a Successful 2021 in Lung Cancer, But Resistance to Available Therapies Remains a Top Concern

The 2021 Year in Review: Updates in Biomarker-Driven Lung Cancer is the digital version of a print publication encompasses some of the biggest data that have read out in bimarker-driven lung cancer in 2021, along with expert insights in article and video format. 