Great Strides Drive Progress Toward Precision Medicine in Lung Cancer Therapy

Lung cancer is the third-most-common cancer in the United States, claiming more lives annually than any other type of the disease.^1,2 Although tobacco use is the leading cause of lung cancer, up to 20% of cases occur in patients who have never smoked but have a family history of the disease or were exposed to naturally occurring radon, workplace chemicals (eg, asbestos, diesel fuel), air pollution, or radiation treatment.^1,3 Less than 25% of patients with lung cancer diagnoses survive more than 5 years, which is substantially lower than the 5-year survival rates for those with breast (89%), prostate (92.9%), or colorectal (65.7%) cancers.²

There are 2 types of lung cancer: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). Each type is categorized into subtypes based on specific cancer cell characteristics (Online Table). Although rates of lung cancer have steadily increased for decades, there has been a recent drop attributed to a decline in tobacco smoking and improvement in the number, type, and quality of the therapeutic options available for lung cancer treatment.

In 2021, the FDA approved 5 new medications for lung cancer and added the disease as an indication for 3 others already commercially available. All but 1 of these medications were for NSCLC, and 4 are oral therapies.

There are niche considerations regarding use of each newly approved medication for lung cancer, representing a shift toward precision medicine in lung cancer treatment. The newly approved medications for NSCLC provide more focused oncologic therapy options that target actional biomarkers for mutations occurring in up to 40% of patients with the disease. The individual prevalence of these mutations in NSCLC is relatively low but often can result in more aggressive cancers with poor outcomes.⁴

Advances in Management of NSCLC

To identify these biomarkers in patients with NSCLC, special testing must assess whether a patient’s cancer is likely to respond to one of these new agents. The duration of therapy with these agents also differs from traditional chemotherapy in that they are often given indefinitely until NSCLC progresses or the patient experiences an intolerable adverse effect (AE). Each medication also has a unique AE profile, although interstitial lung disease and pneumonitis are a concern with every agent that has been approved and/or received an indication for NSCLC since January 2021.^5-11

The 4 novel drugs and new indications for 3 existing agents for NSCLC in 2021 are each directed to different targets. Oral tepotinib targets MET exon 14 skipping alterations seen in 3% to 4% of metastatic NSCLC cases.^4-5,12 Two drugs, the injectable bispecific antibody amivantamab-vmjw and the oral kinase inhibitor mobocertinib, are indicated for patients with EGFR exon 20 insertion mutations.^4,6-7 Like MET exon 14 skipping alterations, these mutations affect 4% to 12% of the overall patient population in NSCLC.⁴

Sotorasib is the first medication approved for any malignancy associated with the KRAS gene seen in approximately 3% to 13% of patients with NSCLC and KRAS G12C mutations.^4,8 Two immune checkpoint inhibitors (ICIs), atezolizumab and cemiplimab-rwlc, received indications for NSCLC. These drugs work by binding to PD-1 or PD-L1, which ultimately removes inhibition of the immune response, upsetting peripheral tolerance.^9-10 Lorlatinib was also granted a new indication for patients with ALK-positive tumors.¹¹

The discovery of oncologic-related mutations has propelled the lung cancer therapeutic pipeline. The introduction of medications that successfully target the mutations is even more impressive; having so many approved in a single year may not have been possible until recently.

Scientists spent more than 30 years trying to develop KRAS-targeted therapies.¹² The KRAS gene was thought to lack a good area to which a drug could attach or anchor, due to its shape and surface.^13-16 Unfortunately, tumors driven by some of these mutations, such as KRAS, are not responsive to other medications, which may partially explain the high mortality rate of lung cancer to date.^14,16

What is interesting about many of the novel and pipeline therapeutics for lung cancer is that they do not appear to cure it but instead work to manage it as if it were a chronic disease such as heart failure or diabetes. For example, anti–PD-1 receptor binding decreases within 2 to 3 months after the last dose of ICIs.¹⁷

For many patients, the use-limiting factor for these medications may not be disease progression but tolerability. Many of these medications can induce effects that would make them more harmful than helpful, which can be related to pharmacology.

For example, the ICIs can produce immune-mediated reactions involving any organ system or tissue that can present during active therapy and even after treatment discontinuation.^9-10 Others may produce severe effects less related to their oncologic mechanisms, such as mobocertinib-induced QTc prolongation or central nervous system effects from lorlatinib.^6,11

Some effects of these novel and pipeline therapeutics may be manageable with dosing modifications. Sotorasib has specific labeled dose reductions for
patients experiencing hepatotoxicity or grade 3 to 4 adverse reactions.⁸

The shift to chronic therapy requires renewed attention to drug-drug and drug-disease interactions. Tepotinib, mobocertinib, sotorasib, and lorlatinib all have drug-drug interactions involving cytochrome P450 3A4, and each of these except for mobocertinib also interacts with P-glycoprotein substrates.^5,6,8,11

Although lung cancer is less common in patients with reproductive potential, particularly women, it is not unheard-of. Patients with reproductive potential should use nonhormonal contraception throughout treatment with tepotinib, mobocertinib, amivantamabvmjw, cemiplimab-rwlc, and atezolizumab; this should be continued for at least 1 week after the last dose in most patients.^5-7,9,10 Women should extend contraception use for 1 month after mobocertinib, 3 months after amivantamab-vmjw, 4 months after cemiplimab-rwlc, and 5 months after atezolizumab.5-7,9,10 Given the similarities in pharmacologic properties of these pipeline medications, it is reasonable that few future medications would pose less of a monitoring requirement for interactions and safety.

Therapeutic Developments in SCLC
In contrast to the advances in management of NSCLC, therapeutic developments for SCLC have not been as successful. Trilaciclib was the only new medication approved for SCLC in 2021.¹⁸ However, the selective cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor is not a traditional chemotherapy agent. The 30-minute infusion is administered proactively to reduce the incidence of myelosuppression from a platinum/etoposidecontaining or topotecan-containing regimen in patients with extensive-stage NSCLC. ¹⁸ It works by maintaining G1 cell cycle arrest of the hematopoietic stem and progenitor cells to protect them from the cytotoxicity from chemotherapy.¹⁸

However, the efficacy data of the trilaciclib are mixed.^19-20 Although the majority of patients in 3 studies investigating trilaciclib for FDA approval were able to complete over 4 cycles of therapy, the drug only performed better than placebo in 1 study evaluating patients receiving a topotecan-containing regimen.¹⁸ However, in the phase 2 study, patients receiving trilaciclib were able to tolerate higher doses of chemotherapy and experienced fewer cycle delays (P = .017 and P = .003, respectively).¹⁹

Another study reported that patients receiving trilaciclib experienced shorter severe neutropenia after cycle 1 (2 days vs 7 days; P < .0001).²⁰ This study also reported that trilaciclib administration resulted in numerically fewer patients requiring the administration of granulocyte colony-stimulating factor agents, erythropoiesis-stimulating agents, platelets, and red blood cell transfusions, as well as less febrile neutropenia and fewer all-cause chemotherapy dose reductions.²⁰ Trilaciclib has a notable AE profile and can cause issues such as hypersensitivities; interstitial lung disease; pneumonitis; pneumonia-related deficiencies in blood calcium, potassium, and phosphate levels; fatigue; increased aspartate aminotransferase levels; and headache.¹⁸

It does appear that for patients able to tolerate trilaciclib, the medication may be cost-effective. A pharmacoeconomic analysis showed a cost savings of $18,840 for patients administered trilaciclib, primarily from a reduced cost in neutropenia and thrombocytopenia management and higher quality-adjusted life.²¹

There are limited but encouraging therapeutics in development for SCLC, primarily for patients who have tried other options that failed. A combination of olaparib, an oral PARP inhibitor, and temozolomide in patients who had previously failed SCLC treatment resulted in a 41.7% overall response rate, a 4.2-month median progression-free survival, and 8.5-month median overall survival.²² Olaparib has also demonstrated efficacy in animals with relapsed SCLC when used in combination with durvalumab, an anti–PD-L1 antibody.

Alisertib and other inhibitors of the Aurora A kinase, an important aspect in mitotic entry and cell cycle regulation, have shown promising results in early studies of patients who have not responded to first-line therapy.²² Fortunately, despite fewer novel approvals than for NSCLC, SCLC has historically been more responsive to more traditional chemotherapeutic options.

Conclusions
For years, lung cancer has remained one of the most frequently diagnosed cancers with a mortality rate that has long surpassed other malignancies. The recent scientific advancements in understanding how lung cancer grows and thrives has provided opportunities for these novel drug targets and therapeutics.

The focus of these scientific advancements continues to be primarily directed toward lung cancers that do not or will not respond to long-standing oncologic therapies. The paradigm shift toward precision medicine introduces the concept of chronic cancer management in a field that has historically focused on remission.

Considering that many recently approved medications are oral therapeutics, with several in the drug pipeline, cancer management is progressing toward holistic care of the patient in the long term. The introduction of these chronic oncologic regimens into the patient’s medication profile will require individualized, diligent, and continuous monitoring for drug-drug interactions and AEs, which vary in scope and severity. However, for a disease with so few treatment options available historically, these important new approaches to therapy for lung cancer offer patients hope where none existed before.

References

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About the Author
Marilyn N. Bulloch, PharmD, BCPS, FCCM, is an associate clinical professor in the Department of Pharmacy Practice at the Auburn University Harrison School of Pharmacy in Alabama.