Pfizer's Third-Generation ALK Inhibitor Lorlatinib Approved in China, Marking the Era of 'Three Generations Together' for ALK+ NSCLC Therapy

Recently, Pfizer announced that the world's first third-generation ALK inhibitor, Lorlatinib (Brand name: Bo Rui Na), has been approved for marketing in China. The indication is for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who are ALK-positive.

At this point, China has achieved "three generations" of ALK inhibitors.

Against the backdrop of China's overall advancement into the era of precision treatment for lung cancer, the field of ALK fusion has seen rapid progress. The three generations of ALK inhibitors have greatly enriched the sequential medication landscape. Meanwhile, due to the significant efficacy of ALK inhibitors in prolonging patients' lives, major pharmaceutical companies are vying to establish their presence in this area.

"Diamond Mutation"

The Anaplastic Lymphoma Kinase (ALK) gene is located on the short arm of chromosome 2 (223) and encodes a transmembrane receptor tyrosine kinase. This kinase consists of 1620 amino acids, belongs to the insulin receptor superfamily, and plays an important role in the development of the central nervous system.

The ALK gene has been found in a series of malignant tumors, including non-small cell lung cancer, anaplastic large cell lymphoma, and neuroblastoma, with rearrangements, point mutations, or amplifications. Among these, chromosomal rearrangements leading to ALK fusion gene mutations through fusion with other genes are the most common.

ALK fusion gene mutations are common in young, non-smoking/lightly smoking patients with lung adenocarcinoma who lack other oncogenic driver mutations. In 2007, the ALK fusion gene was first discovered and confirmed as a driver gene for lung cancer, becoming an important target for non-small cell lung cancer.

Since the incidence of ALK fusion gene mutations is relatively low, the use of corresponding targeted drugs can achieve excellent efficacy and longer survival periods. Therefore, ALK fusion gene mutations are also referred to as "diamond mutations."

▲Mechanism of Action of ALK-TKI, Source: Beta Pharma Prospectus

The incidence and mortality rates of lung cancer have been increasing globally and in China.

In terms of incidence, lung cancer ranks second globally and first in China among all types of cancers, and in terms of mortality, lung cancer ranks first both globally and in China among all types of cancers.

The number of new cases of lung cancer patients in China increased from 813,400 in 2016 to 924,100 in 2020, with a compound annual growth rate of 3.2% from 2016 to 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer incidence, of which 5-7% of patients have ALK mutations.

With the continuous approval and launch of ALK inhibitors in China, the market size of ALK inhibitors in China reached 3 billion yuan in 2020, with a compound annual growth rate of 67.2% from 2016 to 2020; it is expected to reach 8.5 billion yuan by 2025 and 13.9 billion yuan by 2030.

▲China ALK-TKI Drug Market Size, Source: Beta Pharma Prospectus

"Three Generations Under One Roof"

Currently, there are a total of 6 ALK inhibitors available on the market in China.

▲ ALK inhibitors approved for marketing in China, Source: Meibai Healthcare compilation

Crizotinib is the first ALK inhibitor to be marketed globally. It was discovered in 2006 to have an inhibitory effect on tumor cells expressing the EML4-ALK fusion gene, and Phase I clinical trials began. In 2011, it was approved for marketing by the U.S. FDA through a fast-track process, causing a sensation. As a "legendary drug" with the shortest development time from research to market, crizotinib has shown good results in inhibiting targets such as Met, ALK, and ROS. In January 2013, crizotinib was approved for marketing in China.

In the Profile1014 study, the median progression-free survival (PFS) was 10.9 months and the objective response rate (ORR) was 74% among 172 patients treated with crizotinib; in the Profile1029 study, the objective response rate was as high as 88% in East Asian patients with ALK-positive advanced non-small cell lung cancer who received crizotinib as first-line treatment.

However, crizotinib also has some serious shortcomings. Most patients will develop resistance to crizotinib within less than one year of treatment; moreover, due to its difficulty in penetrating the blood-brain barrier, the incidence of brain metastasis in patients treated with crizotinib is as high as 50%.

▲Source: Pfizer Official Website

However, there is no need to worry as second-generation ALK inhibitors have effectively addressed the shortcomings of crizotinib.

In China, there are four second-generation ALK inhibitors on the market, including Ceritinib, Alectinib, Brigatinib, and Ensartinib.

In 2014, Novartis' Ceritinib was launched in the United States, ushering in a new era of second-generation ALK inhibitors. In 2018, Ceritinib was launched in China and was included in the national medical insurance directory through price negotiation in the same year. In 2020, the National Medical Products Administration officially approved Ceritinib monotherapy for patients with locally advanced or metastatic non-small cell lung cancer who are ALK-positive. Since then, Ceritinib has entered the first-line treatment plan for non-small cell lung cancer in China.

In the ASCEND-8 study, the objective response rate (ORR) of ceritinib reached over 75%.

▲Source: Novartis official website

Roche's second-generation ALK inhibitor was developed slightly later than Novartis', but it eventually took the lead. In 2015, Roche's second-generation ALK inhibitor Alectinib was launched in the United States, showing significantly better efficacy than the first-generation products. The emergence of Alectinib gave many people hope of transforming cancer into a chronic disease. In August 2018, Alectinib was approved for marketing in China, and soon in the 2019 guidelines of the Chinese Society of Clinical Oncology, it was recommended as the preferred first-line treatment for ALK-positive non-small cell lung cancer patients.

Based on the results of the global multicenter, randomized, open-label Phase III ALEX study, the median progression-free survival (PFS) assessed by investigators in the Alectinib group was 34.8 months, significantly better than 10.9 months in the Crizotinib group; the 5-year overall survival rate (OS) of Alectinib exceeded 62.5%. Additionally, compared with Crizotinib, Alectinib shows more advantages in preventing brain metastases and delaying disease progression in patients who already have brain metastases.

The ALESIA study, a clinical trial conducted among Asian patients with ALK-positive non-small cell lung cancer, showed that the objective response rate (ORR) of Alectinib was as high as 91%.

▲Source: Roche Official Website

Brigatinib, developed by Takeda Pharmaceutical, was officially approved for marketing by the National Medical Products Administration in March 2022. The indication is for monotherapy in the treatment of patients with locally advanced or metastatic non-small cell lung cancer who are ALK-positive.

According to the results of the international multi-center Phase III clinical study ALTA-1L, brigatinib demonstrated outstanding data in the treatment of brain metastases. The confirmed objective response rate (ORR) for patients with baseline brain metastases was 78%, compared to 26% in the control group; patients with intracranial lesion relief had a sustained relief time of up to 27.9 months, compared to 9.2 months in the control group.

▲Source: Takeda Pharmaceutical Official Website

In the competition among second-generation ALK inhibitors, a shining star of Chinese production has emerged — Ensartinib.

Ensartinib, jointly developed by Betta Pharmaceuticals and its holding subsidiary Xcovery, was officially approved for marketing in China in November 2020, becoming the first domestically produced ALK inhibitor to be approved. In March 2022, ensartinib was approved in China for first-line treatment of ALK-positive locally advanced or metastatic non-small cell lung cancer.

As the first innovative drug targeting ALK in China, the approval and marketing of Ensartinib broke the monopoly of imported drugs and filled the gap in this field. An international multicenter, randomized, open-label clinical study using Crizotinib as a control (eXalt3) showed that the median PFS of patients in the Ensartinib group was 31.3 months, compared to 12.7 months in the Crizotinib group; the objective response rate (ORR) of Ensartinib reached 74%.

▲Source: Betta Pharmaceuticals Official Website

However, second-generation ALK inhibitors still cannot avoid the outcome of drug resistance, and there is a lack of more effective treatment options after resistance develops. In this critical situation, as mentioned at the beginning of this article, third-generation ALK inhibitors have made their brilliant debut.

Previously, Lorlatinib was approved for marketing in the United States and Japan in 2018, and in Europe in 2019; in March 2021, the U.S. FDA approved Lorlatinib for first-line treatment of ALK-positive non-small cell lung cancer.

Since its inception, Lorlatinib has been highly favored. The power of this third-generation targeted drug lies in its ability to overcome all known ALK resistance mutations and penetrate the blood-brain barrier. It can inhibit nine different mutations resistant to Crizotinib and remains highly effective even after resistance to second-generation ALK-TKI drugs. Additionally, Lorlatinib demonstrates strong blood-brain barrier penetration, making it particularly suitable for patients with advanced non-small cell lung cancer who are resistant to other ALK inhibitors.

Based on the clinical data from the Phase III CROWN trial, lorlatinib reduced the risk of disease progression or death by 72% compared to crizotinib. In the lorlatinib group, 78% of patients had no disease progression at 12 months, compared to 39% in the crizotinib group. Additionally, the objective response rate (ORR) for lorlatinib VS crizotinib was 76% VS 58%.

▲Source: Pfizer Official Website

The continuous approval of first, second, and third-generation drugs makes it possible to sequentially use drugs after resistance develops, avoiding the awkward situation of having no drugs available. From the above, we can also see that imported ALK inhibitors still dominate the Chinese market, making the substitution with domestically produced drugs imperative. Fortunately, domestic pharmaceutical companies are quite active in the research and development of ALK inhibitors, with a large number of domestic R&D projects currently underway.

Competition and Future

So far, there are 12 ALK inhibitors undergoing clinical trials in China.

Among them, Qilu Pharmaceutical's second-generation ALK inhibitor Irulac has been submitted for marketing approval and is expected to be approved within the year.

Among the second-generation ALK inhibitors, SY-707 from Shouyao Holdings, TQ-B3139 from Zhengda Tianqing, Furuitinib from Fochon Pharmaceuticals, and XZP-3621 from Xuanzhu Pharmaceuticals are currently in Phase III clinical trials; additionally, Ocatini from Zelgen Biologics, Repotrectinib (TPX-0005) from Zai Lab, and TQ-B3101 from Zhengda Tianqing are in Phase II clinical trials.

Globally, the latest fourth-generation ALK inhibitors have been approved for clinical use.

On March 29, 2022, Nuvalent announced that the U.S. FDA had approved the clinical trial of its new drug NVL-655, with plans to initiate the Phase 1/2 ALKOVE-1 study in patients with ALK-positive non-small cell lung cancer and other solid tumors in the second quarter of 2022.

▲Status of ALK Inhibitors in Clinical Trials in China

Source: Compiled by ChinaBio Healthcare

Conclusion

From the first-generation crizotinib, we have seen the possibility of cancer becoming a chronic disease. The continuous development of one generation after another of ALK inhibitors fully reflects the great scientific spirit that each new generation surpasses the previous one. Living in this era is a blessing for patients. It is hoped that with the help of the six ALK inhibitors already on the market, relevant patients can cross one five-year survival milestone after another. For future developments, MyBioCare will continue to keep an eye on them.